Ubiquitin is a small (8.6
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
)
regulatory protein
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...
found in most tissues of
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
organisms, i.e., it is found
''ubiquitously''. It was discovered in 1975
by Gideon Goldstein and further characterized throughout the late 1970s and 1980s.
Four genes in the
human genome
The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the n ...
code for ubiquitin:
UBB,
UBC
The University of British Columbia (UBC) is a public research university with campuses near Vancouver and in Kelowna, British Columbia. Established in 1908, it is British Columbia's oldest university. The university ranks among the top three ...
,
UBA52
60S ribosomal protein L40 (RPL40) is a protein that in humans is encoded by the ''UBA52'' gene.
Function
Ubiquitin is a highly conserved nuclear and cytoplasmic protein that has a major role in targeting cellular proteins for protein degradat ...
and
RPS27A
40S ribosomal protein S27a is a protein that in humans is encoded by the ''RPS27A'' gene.
Ubiquitin, a highly conserved protein that has a major role in targeting cellular proteins for degradation by the 26S proteosome, is synthesized as a precurs ...
.
The addition of ubiquitin to a substrate protein is called ubiquitylation (or, alternatively, ubiquitination or ubiquitinylation). Ubiquitylation affects proteins in many ways: it can mark them for
degradation
Degradation may refer to:
Science
* Degradation (geology), lowering of a fluvial surface by erosion
* Degradation (telecommunications), of an electronic signal
* Biodegradation of organic substances by living organisms
* Environmental degradatio ...
via the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
, alter their
cellular location, affect their activity, and promote or prevent
protein interactions
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respond ...
.
Ubiquitylation involves three main steps: activation, conjugation, and ligation, performed by
ubiquitin-activating enzyme
Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which (among other things) can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like pro ...
s (E1s),
ubiquitin-conjugating enzyme
Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ''ubiquitin-carrier enzymes'', perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process ...
s (E2s), and
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
s (E3s), respectively. The result of this sequential cascade is to bind ubiquitin to
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues on the protein substrate via an
isopeptide bond,
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residues through a
thioester bond,
serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
and
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
residues through an
ester bond
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
, or the amino group of the protein's
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
via a
peptide bond
In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...
.
The protein modifications can be either a single ubiquitin protein (monoubiquitylation) or a chain of ubiquitin (polyubiquitylation). Secondary ubiquitin molecules are always linked to one of the seven
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues or the N-terminal
methionine
Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
of the previous ubiquitin molecule. These 'linking' residues are represented by a "K" or "M" (the
one-letter amino acid notation
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule as in K48, K29 or M1. The first ubiquitin molecule is covalently bound through its
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
carboxylate group to a particular lysine, cysteine, serine, threonine or N-terminus of the target protein. Polyubiquitylation occurs when the C-terminus of another ubiquitin is linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule, creating a chain. This process repeats several times, leading to the addition of several ubiquitins. Only polyubiquitylation on defined lysines, mostly on K48 and K29, is related to degradation by the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
(referred to as the "molecular kiss of death"), while other polyubiquitylations (e.g. on K63, K11, K6 and M1) and monoubiquitylations may regulate processes such as
endocytic trafficking,
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
,
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
and
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
.
The discovery that ubiquitin chains target proteins to the proteasome, which degrades and recycles proteins, was honored with the
Nobel Prize in Chemistry
)
, image = Nobel Prize.png
, alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
in 2004.
Identification
Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975
as an 8.6
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
protein expressed in all
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cells. The basic functions of ubiquitin and the components of the ubiquitylation pathway were elucidated in the early 1980s at the
Technion by
Aaron Ciechanover
Aaron Ciechanover ( ; he, אהרן צ'חנובר; born October 1, 1947) is an Israeli biologist who won the Nobel Prize in Chemistry for characterizing the method that cells use to degrade and recycle proteins using ubiquitin.
Biography
Early ...
,
Avram Hershko
Avram Hershko ( he, אברהם הרשקו, Avraham Hershko, hu, Herskó Ferenc Ábrahám; born December 31, 1937) is a Hungarian-Israeli biochemist who received the Nobel Prize in Chemistry in 2004.
Biography
He was born Herskó Ferenc in Karc ...
, and
Irwin Rose
Irwin Allan Rose (July 16, 1926 – June 2, 2015) was an American biologist. Along with Aaron Ciechanover and Avram Hershko, he was awarded the 2004 Nobel Prize in Chemistry for the discovery of ubiquitin-mediated protein degradation.
Education ...
for which the
Nobel Prize in Chemistry
)
, image = Nobel Prize.png
, alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
was awarded in 2004.
The ubiquitylation system was initially characterised as an
ATP-dependent
proteolytic
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
system present in cellular extracts. A heat-stable
polypeptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A p ...
present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate
lysozyme
Lysozyme (EC 3.2.1.17, muramidase, ''N''-acetylmuramide glycanhydrolase; systematic name peptidoglycan ''N''-acetylmuramoylhydrolase) is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside ...
in an
ATP- and
Mg2+-dependent process.
Multiple APF-1 molecules were linked to a single
substrate molecule by an
isopeptide linkage, and conjugates were found to be rapidly degraded with the release of free APF-1. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues.
The protein
Ubiquitin is a small
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that exists in all
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s. It performs its myriad functions through conjugation to a large range of target proteins. A variety of
different modifications can occur. The ubiquitin protein itself consists of 76
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s and has a
molecular mass
The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quanti ...
of about 8.6 kDa. Key features include its C-terminal tail and the 7
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues. It is highly conserved throughout eukaryote evolution; human and yeast ubiquitin share 96%
sequence identity
In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Ali ...
.
Genes
Ubiquitin is encoded in mammals by 4 different genes.
UBA52
60S ribosomal protein L40 (RPL40) is a protein that in humans is encoded by the ''UBA52'' gene.
Function
Ubiquitin is a highly conserved nuclear and cytoplasmic protein that has a major role in targeting cellular proteins for protein degradat ...
and
RPS27A
40S ribosomal protein S27a is a protein that in humans is encoded by the ''RPS27A'' gene.
Ubiquitin, a highly conserved protein that has a major role in targeting cellular proteins for degradation by the 26S proteosome, is synthesized as a precurs ...
genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The
UBB and
UBC
The University of British Columbia (UBC) is a public research university with campuses near Vancouver and in Kelowna, British Columbia. Established in 1908, it is British Columbia's oldest university. The university ranks among the top three ...
genes code for polyubiquitin precursor proteins.
Ubiquitylation
Ubiquitylation (also known as ubiquitination or ubiquitinylation) is an enzymatic
post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
in which a ubiquitin protein is attached to a
substrate protein. This process most commonly binds the last
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
of ubiquitin (
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
76) to a
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residue on the substrate. An
isopeptide bond is formed between the
carboxyl
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
group (COO
−) of the ubiquitin's glycine and the epsilon-
amino group
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
(ε-) of the substrate's lysine.
Trypsin cleavage of a ubiquitin-conjugated substrate leaves a di-glycine "remnant" that is used to identify the site of ubiquitylation.
Ubiquitin can also be bound to other sites in a protein which are electron-rich
nucleophile
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
s, termed "non-canonical ubiquitylation".
This was first observed with the
amine group
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
of a protein's
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
being used for ubiquitylation, rather than a lysine residue, in the protein
MyoD
MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins know ...
and has been observed since in 22 other proteins in multiple species,
including ubiquitin itself.
There is also increasing evidence for nonlysine residues as ubiquitylation targets using non-amine groups, such as the
sulfhydryl group
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
on cysteine,
and the
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
group on threonine and serine.
The end result of this process is the addition of one ubiquitin molecule (monoubiquitylation) or a chain of ubiquitin molecules (polyubiquitination) to the substrate protein.
Ubiquitination requires three types of enzyme:
ubiquitin-activating enzyme
Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which (among other things) can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like pro ...
s,
ubiquitin-conjugating enzyme
Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ''ubiquitin-carrier enzymes'', perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process ...
s, and
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
s, known as E1s, E2s, and E3s, respectively. The process consists of three main steps:
# Activation: Ubiquitin is activated in a two-step reaction by an E1
ubiquitin-activating enzyme
Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which (among other things) can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like pro ...
, which is dependent on
ATP. The initial step involves production of a ubiquitin-adenylate intermediate. The E1 binds both ATP and ubiquitin and catalyses the acyl-adenylation of the
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
of the ubiquitin molecule. The second step transfers ubiquitin to an
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residue, with release of
AMP #REDIRECT Amp
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
. This step results in a
thioester
In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...
linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine
sulfhydryl group
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
.
The human genome contains two genes that produce enzymes capable of activating ubiquitin:
UBA1
Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the ''UBA1'' gene. UBA1 participates in ubiquitin#ubiquitination, ubiquitination and the NEDD8 pathway for protein folding and Biodegradation, degradati ...
and
UBA6.
# Conjugation: E2
ubiquitin-conjugating enzyme
Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ''ubiquitin-carrier enzymes'', perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process ...
s catalyse the transfer of ubiquitin from E1 to the
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
cysteine of the E2 via a trans(thio)esterification reaction. In order to perform this reaction, the E2 binds to both activated ubiquitin and the E1 enzyme. Humans possess 35 different E2 enzymes, whereas other
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
organisms have between 16 and 35. They are characterised by their highly conserved structure, known as the ubiquitin-conjugating catalytic (UBC) fold.
![Glycine lysine isopeptide v2](https://upload.wikimedia.org/wikipedia/commons/9/9a/Glycine_lysine_isopeptide_v2.svg)
# Ligation: E3
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
s catalyse the final step of the ubiquitination cascade. Most commonly, they create an isopeptide bond between a lysine of the target protein and the C-terminal glycine of ubiquitin. In general, this step requires the activity of one of the hundreds of E3s. E3 enzymes function as the
substrate recognition modules of the system and are capable of interaction with both E2 and substrate. Some E3 enzymes also activate the E2 enzymes. E3 enzymes possess one of two
domains: the homologous to the E6-AP carboxyl terminus (
HECT
or Hector was a Japanese video game developer and publisher. It had a Virtual Boy game in development, entitled ''Virtual Battle Ball''; however, it was eventually canceled.
List of games
*'' Shogun''
*''Emoyan no 10-bai Pro Yakyuu''
*''Great ...
) domain and the really interesting new gene (
RING
Ring may refer to:
* Ring (jewellery), a round band, usually made of metal, worn as ornamental jewelry
* To make a sound with a bell, and the sound made by a bell
:(hence) to initiate a telephone connection
Arts, entertainment and media Film and ...
) domain (or the closely related U-box domain). HECT domain E3s transiently bind ubiquitin in this process (an obligate thioester intermediate is formed with the active-site cysteine of the E3), whereas RING domain E3s catalyse the direct transfer from the E2 enzyme to the substrate.
The
anaphase-promoting complex
Anaphase-promoting complex (also called the cyclosome or APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cull ...
(APC) and the
SCF complex
Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has impo ...
(for Skp1-Cullin-F-box protein complex) are two examples of multi-
subunit E3s involved in recognition and ubiquitination of specific target proteins for degradation by the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
.
In the ubiquitination cascade, E1 can bind with many E2s, which can bind with hundreds of E3s in a hierarchical way. Having levels within the cascade allows tight regulation of the ubiquitination machinery.
Other ubiquitin-like proteins (UBLs) are also modified via the E1–E2–E3 cascade, although variations in these systems do exist.
E4 enzymes, or ubiquitin-chain elongation factors, are capable of adding pre-formed polyubiquitin chains to substrate proteins. For example, multiple monoubiquitylation of the tumor suppressor
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
by
Mdm2 can be followed by addition of a polyubiquitin chain using
p300 and CBP.
Types
Ubiquitination affects cellular process by regulating the degradation of proteins (via the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
and
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
), coordinating the
cellular localization of proteins, activating and inactivating proteins, and modulating
protein–protein interaction
Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and th ...
s.
These effects are mediated by different types of substrate ubiquitination, for example the addition of a single ubiquitin molecule (monoubiquitination) or different types of ubiquitin chains (polyubiquitination).
Monoubiquitination
Monoubiquitination is the addition of one ubiquitin molecule to one substrate protein residue. Multi-monoubiquitination is the addition of one ubiquitin molecule to multiple substrate residues. The monoubiquitination of a protein can have different effects to the polyubiquitination of the same protein. The addition of a single ubiquitin molecule is thought to be required prior to the formation of polyubiquitin chains.
Monoubiquitination affects cellular processes such as
membrane trafficking Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory ...
,
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
and
viral budding
Viral shedding is the expulsion and release of virus progeny following successful reproduction during a host (biology), host cell (biology), cell infection. Once replication has been completed and the host cell is exhausted of all resources in ma ...
.
Polyubiquitin chains
![diubiquitin-lysine-63](https://upload.wikimedia.org/wikipedia/commons/f/f4/Diubiquitin-lysine-63.png)
Polyubiquitination is the formation of a ubiquitin chain on a single lysine residue on the substrate protein. Following addition of a single ubiquitin moiety to a protein substrate, further ubiquitin molecules can be added to the first, yielding a polyubiquitin chain.
These chains are made by linking the glycine residue of a ubiquitin molecule to a lysine of ubiquitin bound to a substrate. Ubiquitin has seven
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues and an
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
that serves as points of ubiquitination; they are K6, K11, K27, K29, K33, K48, K63 and M1, respectively.
Lysine 48-linked chains were the first identified and are the best-characterised type of ubiquitin chain. K63 chains have also been well-characterised, whereas the function of other lysine chains, mixed chains, branched chains, M1-linked linear chains, and heterologous chains (mixtures of ubiquitin and other ubiquitin-like proteins) remains more unclear.
Lysine 48-linked polyubiquitin chains target proteins for destruction, by a process known as
proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
. Multi-ubiquitin chains at least four ubiquitin molecules long must be attached to a lysine residue on the condemned protein in order for it to be recognised by the
26S proteasome.
This is a barrel-shape structure comprising a central proteolytic core made of four ring structures, flanked by two cylinders that selectively allow entry of ubiquitinated proteins. Once inside, the proteins are rapidly degraded into small
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
s (usually 3–25 amino acid residues in length). Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use.
Although the majority of protein substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome.
The polyubiquitin chains are recognised by a subunit of the proteasome: S5a/Rpn10. This is achieved by a
ubiquitin-interacting motif (UIM) found in a hydrophobic patch in the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
region of the S5a/Rpn10 unit.
Lysine 63-linked chains are not associated with proteasomal degradation of the substrate protein. Instead, they allow the coordination of other processes such as
endocytic trafficking,
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
,
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
, and
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
.
In cells, lysine 63-linked chains are bound by the
ESCRT-0 complex, which prevents their binding to the proteasome. This complex contains two proteins, Hrs and STAM1, that contain a UIM, which allows it to bind to lysine 63-linked chains.
Less is understood about atypical (non-lysine 48-linked) ubiquitin chains but research is starting to suggest roles for these chains.
There is evidence to suggest that atypical chains linked by lysine 6, 11, 27, 29 and methionine 1 can induce proteasomal degradation.
Branched ubiquitin chains containing multiple linkage types can be formed.
The function of these chains is unknown.
Structure
Differently linked chains have specific effects on the protein to which they are attached, caused by differences in the conformations of the protein chains. K29-, K33-,
K63- and M1-linked chains have a fairly linear conformation; they are known as open-conformation chains. K6-, K11-, and K48-linked chains form closed conformations. The ubiquitin molecules in open-conformation chains do not interact with each other, except for the covalent
isopeptide bonds linking them together. In contrast, the closed conformation chains have interfaces with interacting residues. Altering the chain conformations exposes and conceals different parts of the ubiquitin protein, and the different linkages are recognized by proteins that are specific for the unique
topologies
In mathematics, topology (from the Greek words , and ) is concerned with the properties of a geometric object that are preserved under continuous deformations, such as stretching, twisting, crumpling, and bending; that is, without closing ho ...
that are intrinsic to the linkage. Proteins can specifically bind to ubiquitin via
ubiquitin-binding domains (UBDs). The distances between individual ubiquitin units in chains differ between lysine 63- and 48-linked chains. The UBDs exploit this by having small spacers between
ubiquitin-interacting motifs that bind lysine 48-linked chains (compact ubiquitin chains) and larger spacers for lysine 63-linked chains. The machinery involved in recognising polyubiquitin chains can also differentiate between K63-linked chains and M1-linked chains, demonstrated by the fact that the latter can induce proteasomal degradation of the substrate.
Function
The ubiquitination system functions in a wide variety of cellular processes, including:
*
Antigen processing Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This pro ...
*
Apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
*
Biogenesis
Spontaneous generation is a superseded scientific theory that held that living creatures could arise from nonliving matter and that such processes were commonplace and regular. It was hypothesized that certain forms, such as fleas, could arise ...
of organelles
* Cell cycle and division
*
DNA transcription
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...
and repair
* Differentiation and development
* Immune response and inflammation
* Neural and muscular degeneration
* Maintenance of
pluripotency Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta.
According to Latin terms, Pluripotentia means the ability for many thin ...
* Morphogenesis of neural networks
* Modulation of cell surface receptors, ion channels and the secretory pathway
* Response to stress and extracellular modulators
*
Ribosome biogenesis
Ribosome biogenesis is the process of making ribosomes. In prokaryotes, this process takes place in the cytoplasm with the transcription of many ribosome gene operons. In eukaryotes, it takes place both in the cytoplasm and in the nucleolus. I ...
* Viral infection
Membrane proteins
Multi-monoubiquitination can mark
transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
s (for example,
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
) for removal from
membranes
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
(internalisation) and fulfil several signalling roles within the cell. When cell-surface transmembrane molecules are tagged with ubiquitin, the subcellular localization of the protein is altered, often targeting the protein for destruction in lysosomes. This serves as a negative feedback mechanism, because often the stimulation of receptors by ligands increases their rate of ubiquitination and internalisation. Like monoubiquitination, lysine 63-linked polyubiquitin chains also has a role in the trafficking some membrane proteins.
Genomic maintenance
Proliferating cell nuclear antigen
Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling the DNA, whe ...
(PCNA) is a protein involved in
DNA synthesis
DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occur ...
. Under normal physiological conditions PCNA is
sumoylated (a similar post-translational modification to ubiquitination). When
DNA is damaged by
ultra-violet radiation
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
or chemicals, the
SUMO
is a form of competitive full-contact wrestling where a ''rikishi'' (wrestler) attempts to force his opponent out of a circular ring (''dohyō'') or into touching the ground with any body part other than the soles of his feet (usually by thr ...
molecule that is attached to a lysine residue is replaced by ubiquitin. Monoubiquitinated PCNA recruits
polymerase
A polymerase is an enzyme ( EC 2.7.7.6/7/19/48/49) that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using base- ...
s that can carry out DNA synthesis with damaged DNA; but this is very error-prone, possibly resulting in the synthesis of mutated DNA. Lysine 63-linked polyubiquitination of PCNA allows it to perform a less error-prone mutation bypass known by the template switching pathway.
Ubiquitination of
histone H2AX is involved in
DNA damage recognition of DNA double-strand breaks. Lysine 63-linked polyubiquitin chains are formed on H2AX histone by the
E2/E3 ligase pair, Ubc13-Mms2/RNF168.
This K63 chain appears to recruit RAP80, which contains a UIM, and
RAP80 then helps localize
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
. This pathway will eventually recruit the necessary proteins for
homologous recombination repair
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
.
Transcriptional regulation
Histones
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
can be ubiquitinated and this is usually in the form of monoubiquitination (although polyubiquitinated forms do occur). Histone ubiquitination alters chromatin structure and allows the access of enzymes involved in transcription. Ubiquitin on histones also acts as a binding site for proteins that either activate or inhibit transcription and also can induce further post-translational modifications of the protein. These effects can all modulate the transcription of genes.
Deubiquitination
Deubiquitinating enzyme
Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin f ...
s (DUBs) oppose the role of ubiquination by removing ubiquitin from substrate proteins. They are
cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal Chund ...
s that cleave the
amide bond between the two proteins. They are highly specific, as are the E3 ligases that attach the ubiquitin, with only a few substrates per enzyme. They can cleave both
isopeptide (between ubiquitin and lysine) and
peptide bond
In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...
s (between ubiquitin and the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
).
In addition to removing ubiquitin from substrate proteins, DUBs have many other roles within the cell. Ubiquitin is either expressed as multiple copies joined in a chain (polyubiquitin) or attached to ribosomal subunits. DUBs cleave these proteins to produce active ubiquitin. They also recycle ubiquitin that has been bound to small
nucleophilic
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
molecules during the ubiquitination process. Monoubiquitin is formed by DUBs that cleave ubiquitin from free polyubiquitin chains that have been previously removed from proteins.
Ubiquitin-binding domains
Ubiquitin-binding domains (UBDs) are modular protein domains that non-covalently bind to ubiquitin, these motifs control various cellular events. Detailed molecular structures are known for a number of UBDs, binding specificity determines their mechanism of action and regulation, and how it regulates cellular proteins and processes.
Disease associations
Pathogenesis
The ubiquitin pathway has been implicated in the pathogenesis of a wide range of diseases and disorders including:
*
Neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
* Infection and immunity
*
Genetic disorders
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
*
Cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
Neurodegeneration
Ubiquitin is implicated in neurodegenerative diseases associated with proteostasis dysfunction, including
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
,
motor neurone disease
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
,
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
and
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
Transcript variants encoding different isoforms of
ubiquilin-1 are found in lesions associated with
Alzheimer's
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
and
Parkinson's
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
disease. Higher levels of ubiquilin in the brain have been shown to decrease malformation of
amyloid precursor protein (APP), which plays a key role in triggering Alzheimer's disease.
[
*] Conversely, lower levels of ubiquilin-1 in the brain have been associated with increased malformation of
APP.
A frameshift mutation in
ubiquitin B
Ubiquitin is a protein that in humans is encoded by the ''UBB'' gene.
Function
Ubiquitin is one of the most conserved proteins known in eukaryotic organisms. Ubiquitin is required for ATP-dependent, non-lysosomal intracellular protein degradat ...
can result in a truncated peptide missing the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
. This abnormal peptide, known as
UBB+1, has been shown to accumulate selectively in
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and other
tauopathies
Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known ...
.
Infection and immunity
Ubiquitin and ubiquitin-like molecules extensively regulate immune
signal transduction pathways
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
at virtually all stages, including steady-state repression, activation during infection, and attenuation upon clearance. Without this regulation, immune activation against
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s may be defective, resulting in chronic disease or death. Alternatively, the immune system may become hyperactivated and organs and tissues may be subjected to
autoimmune damage.
On the other hand,
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
es must block or redirect host cell processes including
immunity
Immunity may refer to:
Medicine
* Immunity (medical), resistance of an organism to infection or disease
* ''Immunity'' (journal), a scientific journal published by Cell Press
Biology
* Immune system
Engineering
* Radiofrequence immunity desc ...
to effectively replicate, yet many viruses relevant to disease have informationally limited
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
s. Because of its very large number of roles in the cell, manipulating the ubiquitin system represents an efficient way for such viruses to block, subvert or redirect critical host cell processes to support their own replication.
The retinoic acid-inducible gene I (
RIG-I
RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infect ...
) protein is a primary immune system sensor for viral and other invasive RNA in human cells. The RIG-I-like receptor (
RLR) immune signaling pathway is one of the most extensively studied in terms of the role of ubiquitin in immune regulation.
Genetic disorders
*
Angelman syndrome
Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...
is caused by a disruption of ''
UBE3A
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the ''UBE3A'' gene. This enzyme is involved in targeting proteins for degradation within cells.
Protein degradation ...
'', which encodes a ubiquitin ligase (E3) enzyme termed E6-AP.
*
Von Hippel–Lindau syndrome involves disruption of a ubiquitin E3 ligase termed the VHL tumor suppressor, or ''
VHL'' gene.
*
Fanconi anemia
Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of nor ...
: Eight of the thirteen identified genes whose disruption can cause this disease encode proteins that form a large ubiquitin ligase (E3) complex.
*
3-M syndrome is an autosomal-recessive growth retardation disorder associated with mutations of the
Cullin7 E3 ubiquitin ligase.
Diagnostic use
Immunohistochemistry
Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
using
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
to ubiquitin can identify abnormal accumulations of this protein inside cells, indicating a disease process. These protein accumulations are referred to as
inclusion bodies
Inclusion bodies are aggregates of specific types of protein found in neurons, a number of tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also found in muscle cells ...
(which is a general term for any microscopically visible collection of abnormal material in a cell). Examples include:
*
Neurofibrillary tangles in
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
*
Lewy body
Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and ...
in
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
*
Pick bodies
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
in
Pick's disease
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
* Inclusions in
motor neuron disease
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
and
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
*
Mallory bodies in
alcoholic liver disease
Alcoholic liver disease (ALD), also called alcohol-related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis ...
*
Rosenthal fiber
A Rosenthal fiber is a thick, elongated, worm-like or "corkscrew" eosinophilic (pink) bundle that is found on staining of brain tissue in the presence of long-standing gliosis, occasional tumors, and some metabolic disorders.
Associated conditi ...
s in
astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...
s
Link to cancer
Post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
of proteins is a generally used mechanism in
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cell signaling.
Ubiquitination, or ubiquitin conjugation to
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s, is a crucial process for
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
progression and
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
and development. Although ubiquitination usually serves as a signal for protein degradation through the
26S proteasome, it could also serve for other fundamental cellular processes,
e.g. in
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
, enzymatic activation and DNA repair. Moreover, since ubiquitination functions to tightly regulate the cellular level of
cyclins, its misregulation is expected to have severe impacts. First evidence of the importance of the ubiquitin/proteasome pathway in
oncogenic
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
processes was observed due to the high antitumor activity of proteasome inhibitors.
Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or present in human carcinoma.
Malignancies could be developed through
loss of function mutation directly at the
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
, increased activity of ubiquitination, and/or indirect attenuation of ubiquitination due to mutation in related proteins.
Direct loss of function mutation of E3 ubiquitin ligase
Renal cell carcinoma
The VHL (
Von Hippel–Lindau) gene encodes a component of an
E3 ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
. VHL complex targets member of the
hypoxia-inducible transcription factor family (HIF) for degradation by interacting with the oxygen-dependent destruction domain under normoxic condition. HIF activates downstream targets such as the
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF), promoting
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
. Mutations in VHL prevent degradation of HIF and thus lead to the formation of
hypervascular
Hypervascularity is an increased number or concentration of blood vessels.
In Graves disease, the thyroid gland is hypervascular, which can help in differentiating the condition from thyroiditis.
90% of thyroid papillary carcinoma cases are hy ...
lesions and renal tumors.
Breast cancer
The ''
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
'' gene is another tumor suppressor gene in humans which encodes the BRCA1 protein that is involved in response to DNA damage. The protein contains a
RING
Ring may refer to:
* Ring (jewellery), a round band, usually made of metal, worn as ornamental jewelry
* To make a sound with a bell, and the sound made by a bell
:(hence) to initiate a telephone connection
Arts, entertainment and media Film and ...
motif with E3 Ubiquitin Ligase activity. BRCA1 could form dimer with other molecules, such as
BARD1
BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the ''BARD1'' gene. The human BARD1 protein is 777 amino acids long and contains a RING finger domain (residues 46-90), four ankyrin repeats (residues 420-555), and t ...
and
BAP1
BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the ''BAP1'' gene. ''BAP1'' encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (U ...
, for its ubiquitination activity. Mutations that affect the ligase function are often found and associated with various cancers.
Cyclin E
As processes in cell cycle progression is the most fundamental processes for cellular growth and differentiation, and are the most common to be altered in human carcinomas, it is expected for cell cycle-regulatory proteins to be under tight regulation. The level of cyclins, as the name suggests, are high only at certain time point during cell cycle. This is achieved by continuous control of cyclins or CDKs levels through ubiquitination and degradation. When cyclin E is partnered with CDK2 and gets phosphorylated, an SCF-associated
F-box protein
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.
Core c ...
Fbw7 recognizes the complex and thus targets it for degradation. Mutations in Fbw7 have been found in more than 30% of human tumors, characterizing it as a tumor suppressor protein.
Increased ubiquitination activity
Cervical cancer
Oncogenic types of the
human papillomavirus (HPV) are known to hijack cellular ubiquitin-
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
pathway for viral infection and replication. The E6 proteins of HPV will bind to the N-terminus of the cellular E6-AP E3 ubiquitin ligase, redirecting the complex to bind
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, a well-known tumor suppressor gene that inactivation is found in many types of cancer.
Thus, p53 undergoes ubiquitination and proteasome-mediated degradation. Meanwhile, E7, another one of the early-expressed HPV genes, will bind to
Rb, also a tumor suppressor gene, mediating its degradation.
The loss of p53 and Rb in cells allows limitless cell proliferation to occur.
p53 regulation
Gene amplification often occur in various tumor cases, including of
''MDM2'', a gene encodes for a RING E3 Ubiquitin ligase responsible for downregulation of p53 activity. MDM2 targets p53 for ubiquitination and proteasomal degradation thus keeping its level appropriate for normal cell condition. Overexpression of MDM2 causes loss of p53 activity and therefore allowing cells to have a limitless replicative potential.
p27
Another gene that is a target of gene amplification is ''
SKP2
S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the ''SKP2'' gene.
Structure and function
Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-1 ...
''. SKP2 is an
F-box protein
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.
Core c ...
that roles in substrate recognition for ubiquitination and degradation. SKP2 targets
p27Kip-1, an inhibitor of cyclin-dependent kinases (
CDKs). CDKs2/4 partner with the
cyclins E/D, respectively, family of cell cycle regulator to control cell cycle progression through the G1 phase. Low level of p27
Kip-1 protein is often found in various cancers and is due to overactivation of ubiquitin-mediated proteolysis through overexpression of SKP2.
Efp
Efp, or estrogen-inducible RING-finger protein, is an E3 ubiquitin ligase that overexpression has been shown to be the major cause of
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
-independent
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
.
Efp's substrate is
14-3-3 protein which negatively regulates cell cycle.
Evasion of ubiquitination
Colorectal cancer
The gene associated with
colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
is the
adenomatous polyposis coli
Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the ''APC'' gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-c ...
(APC), which is a classic
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
. APC gene product targets
beta-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...
for degradation via ubiquitination at the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
, thus regulating its cellular level. Most colorectal cancer cases are found with mutations in the APC gene. However, in cases where APC gene is not mutated, mutations are found in the N-terminus of beta-catenin which renders it ubiquitination-free and thus increased activity.
Glioblastoma
As the most aggressive cancer originated in the brain, mutations found in patients with
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
are related to the deletion of a part of the extracellular domain of the
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recept ...
(EGFR). This deletion causes
CBL E3 ligase unable to bind the receptor for its recycling and degradation via a ubiquitin-lysosomal pathway. Thus, EGFR is constitutively active in the cell membrane and activates its downstream effectors that are involved in cell proliferation and migration.
Phosphorylation-dependent ubiquitination
The interplay between ubiquitination and
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
has been an ongoing research interest since phosphorylation often serves as a marker where ubiquitination leads to degradation.
Moreover, ubiquitination can also act to turn on/off the
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
activity of a protein. The critical role of phosphorylation is largely underscored in the activation and removal of autoinhibition in
Cbl protein.
Cbl is an E3 ubiquitin ligase with a RING finger domain that interacts with its
tyrosine kinase binding (TKB) domain, preventing interaction of the RING domain with an
E2 ubiquitin-conjugating enzyme. This intramolecular interaction is an autoinhibition regulation that prevents its role as a negative regulator of various growth factors and
tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
signaling and
T-cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
activation.
Phosphorylation of
Y363 relieves the autoinhibition and enhances binding to E2.
Mutations that renders the Cbl protein dysfunctional due to the loss of its ligase/tumor suppressor function and maintenance of its positive signaling/oncogenic function have been shown to cause development of cancer.
As a drug target
Screening for ubiquitin ligase substrates
Deregulation of E3-substrate interactions is a key cause of many human disorders, therefore identifying E3 ligase substrates is crucial. In 2008, 'Global Protein Stability (GPS) Profiling' was developed to discover E3 ubiquitin ligase substrates.
This high-throughput system made use of reporter proteins fused with thousands of potential substrates independently. By inhibition of the ligase activity (through the making of Cul1 dominant negative thus renders ubiquitination not to occur), increased reporter activity shows that the identified substrates are being accumulated. This approach added a large number of new substrates to the list of E3 ligase substrates.
Possible therapeutic applications
Blocking of specific substrate recognition by the E3 ligases, e.g.
bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
.
Challenge
Finding a specific molecule that selectively inhibits the activity of a certain E3 ligase and/or the protein–protein interactions implicated in the disease remains as one of the important and expanding research area. Moreover, as ubiquitination is a multi-step process with various players and intermediate forms, consideration of the much complex interactions between components needs to be taken heavily into account while designing the small molecule inhibitors.
Similar proteins
Ubiquitin is the most-understood post-translation modifier, however, several family of
ubiquitin-like protein
Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class ...
s (UBLs) are found can modify cellular targets in a parallel but distinct route. Known UBLs include: small ubiquitin-like modifier (
SUMO
is a form of competitive full-contact wrestling where a ''rikishi'' (wrestler) attempts to force his opponent out of a circular ring (''dohyō'') or into touching the ground with any body part other than the soles of his feet (usually by thr ...
), ubiquitin cross-reactive protein (UCRP, also known as interferon-stimulated gene-15
ISG15
Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ''ISG15'' gene. ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellul ...
), ubiquitin-related modifier-1 (
URM1
Ubiquitin-related modifier-1 (URM1) is a ubiquitin-like protein that modifies proteins in the yeast ubiquitin-like urmylation pathway. Structural comparisons and phylogenetic analysis of the ubiquitin superfamily has indicated that Urm1 has the mo ...
), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (
NEDD8
NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a proc ...
, also called Rub1 in ''
S. cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have bee ...
''), human leukocyte antigen F-associated (
FAT10), autophagy-8 (
ATG8
Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for aut ...
) and -12 (
ATG12
Autophagy related 12 is a protein that in humans is encoded by the ''ATG12'' gene.
Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autopha ...
), Few ubiquitin-like protein (
FUB1), MUB (membrane-anchored UBL),
ubiquitin fold-modifier-1 (
UFM1
Ubiquitin-fold modifier 1, also known as UFM1, is a protein which in humans is encoded by the ''UFM1'' gene.
UFM1 is a ubiquitin-like protein that is conjugated to target proteins by E1-like activating enzyme UBE1DC1, UBA5 and E2-like conjugating ...
) and ubiquitin-like protein-5 (
UBL5, which is but known as homologous to ubiquitin-1
ub1in ''
S. pombe
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...
'').
Although these proteins share only modest primary sequence identity with ubiquitin, they are closely related three-dimensionally. For example, SUMO shares only 18% sequence identity, but they contain the same structural fold. This fold is called "ubiquitin fold". FAT10 and UCRP contain two. This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise a ubiquitin-like domain, e.g. the ''S. cerevisiae'' spindle pole body duplication protein, Dsk2, and NER protein, Rad23, both contain N-terminal ubiquitin domains.
These related molecules have novel functions and influence diverse biological processes. There is also cross-regulation between the various conjugation pathways, since some proteins can become modified by more than one UBL, and sometimes even at the same lysine residue. For instance, SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates. Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome but rather function in diverse regulatory activities. Attachment of UBLs might, alter substrate conformation, affect the affinity for ligands or other interacting molecules, alter substrate localization, and influence protein stability.
UBLs are structurally similar to ubiquitin and are processed, activated, conjugated, and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. UBLs are also translated with C-terminal extensions that are processed to expose the invariant C-terminal LRGG. These modifiers have their own specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes that conjugate the UBLs to intracellular targets. These conjugates can be reversed by UBL-specific isopeptidases that have similar mechanisms to that of the deubiquitinating enzymes.
Within some species, the recognition and destruction of sperm mitochondria through a mechanism involving ubiquitin is responsible for sperm mitochondria's disposal after fertilization occurs.
Prokaryotic origins
Ubiquitin is believed to have descended from bacterial proteins similar to
ThiS
This may refer to:
* ''This'', the singular proximal demonstrative pronoun
Places
* This, or ''Thinis'', an ancient city in Upper Egypt
* This, Ardennes, a commune in France
People with the surname
* Hervé This, French culinary chemist Arts, e ...
()
or
MoaD ().
These prokaryotic proteins, despite having little sequence identity (ThiS has 14% identity to ubiquitin), share the same protein fold. These proteins also share sulfur chemistry with ubiquitin. MoaD, which is involved in
molybdopterin
Molybdopterins are a class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes. Synonyms for molybdopterin are: MPT and pyranopterin-dithiolate. The nomenclature for this biomolecule can be confusing: Molybdopter ...
biosynthesis, interacts with MoeB, which acts like an
E1 ubiquitin-activating enzyme for MoaD, strengthening the link between these prokaryotic proteins and the ubiquitin system. A similar system exists for ThiS, with its E1-like enzyme
ThiF. It is also believed that the ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'' protein
Urm1
Ubiquitin-related modifier-1 (URM1) is a ubiquitin-like protein that modifies proteins in the yeast ubiquitin-like urmylation pathway. Structural comparisons and phylogenetic analysis of the ubiquitin superfamily has indicated that Urm1 has the mo ...
, a ubiquitin-related modifier, is a "molecular fossil" that connects the evolutionary relation with the prokaryotic ubiquitin-like molecules and ubiquitin.
Archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
have a functionally closer homolog of the ubiquitin modification system, where "sampylation" with SAMPs (small archaeal modifier proteins) is performed. The sampylation system only uses E1 to guide proteins to the
proteosome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
.
Proteoarchaeota
"Proteoarchaeota" are a proposed archaeal kingdom thought to be closely related to the Eukaryotes.Approximately the same group is sometimes referred to as TACK after the initial letters of its early-found daughter clades: Thaumarchaeota (now Nitr ...
, which are related to the ancestor of eukaryotes, possess all of the E1, E2, and E3 enzymes plus a regulated Rpn11 system. Unlike SAMP which are more similar to ThiS or MoaD, Proteoarchaeota ubiquitin are most similar to eukaryotic homologs.
Prokaryotic ubiquitin-like protein (Pup) and ubiquitin bacterial (UBact)
Prokaryotic ubiquitin-like protein (Pup) is a
functional analog of ubiquitin which has been found in the
gram-positive
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
Gram-positive bacte ...
bacterial phylum
Actinomycetota
The ''Actinomycetota'' (or ''Actinobacteria'') are a phylum of all gram-positive bacteria. They can be terrestrial or aquatic. They are of great economic importance to humans because agriculture and forests depend on their contributions to soi ...
. It serves the same function (targeting proteins for degradations), although the enzymology of ubiquitination and pupylation is different, and the two families share no homology. In contrast to the three-step reaction of ubiquitination, pupylation requires two steps, therefore only two enzymes are involved in pupylation.
In 2017, homologs of Pup were reported in five phyla of
gram-negative
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
bacteria, in seven candidate bacterial phyla and in one archaeon
The sequences of the Pup homologs are very different from the sequences of Pup in gram-positive bacteria and were termed
Ubiquitin bacterial (UBact), although the distinction has yet not been proven to be phylogenetically supported by a separate evolutionary origin and is without experimental evidence.
The finding of the Pup/UBact-proteasome system in both gram-positive and gram-negative bacteria suggests that either the Pup/UBact-proteasome system evolved in bacteria prior to the split into gram positive and negative clades over 3000 million years ago or,
that these systems were acquired by different bacterial lineages through
horizontal gene transfer
Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between Unicellular organism, unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offsprin ...
(s) from a third, yet unknown, organism. In support of the second possibility, two ''UBact'' loci were found in the genome of an uncultured anaerobic methanotrophic Archaeon (ANME-1;locu
CBH38808.1and locu
CBH39258.1.
Human proteins containing ubiquitin domain
These include ubiquitin-like proteins.
ANUBL1;
BAG1
BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the ''BAG1'' gene.
Function
The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein ...
;
BAT3/BAG6;
C1orf131
Uncharacterized protein C1orf131 is a protein that in humans is encoded by the gene ''C1orf131''. The first ortholog of this protein was discovered in humans. Subsequently, through the use of algorithms and bioinformatics, homologs of C1orf131 ha ...
;
DDI1
DNA-damage inducible 1 homolog 1 (S. cerevisiae) is a protein. In humans it is encoded by the DDI1 gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ...
;
DDI2
DDI may stand for:
Companies and organizations
* DD International, international TV channel in India
* Development Dimensions International, a talent management company
* Direct Democracy Ireland, a political party in Ireland
* KDDI, formerly D ...
;
FAU;
HERPUD1
Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein is a protein that in humans is encoded by the ''HERPUD1'' gene.
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the ER ...
;
HERPUD2;
HOPS
Hops are the flowers (also called seed cones or strobiles) of the hop plant ''Humulus lupulus'', a member of the Cannabaceae family of flowering plants. They are used primarily as a bittering, flavouring, and stability agent in beer, to whi ...
;
IKBKB
IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the ''IKBKB'' (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene.
Function
IKK-β is an enzy ...
;
ISG15
Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ''ISG15'' gene. ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellul ...
;
LOC391257;
MIDN;
NEDD8
NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a proc ...
;
OASL;
PARK2
Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the ''PARK2'' gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub ...
;
RAD23A
UV excision repair protein RAD23 homolog A is a protein that in humans is encoded by the ''RAD23A'' gene.
Function
The protein encoded by this gene is one of two human homologs of ''Saccharomyces cerevisiae'' Rad23, a protein involved in nucl ...
;
RAD23B
UV excision repair protein RAD23 homolog B is a protein that in humans is encoded by the ''RAD23B'' gene.
Function
The protein encoded by this gene is one of two human homologs of Saccharomyces cerevisiae Rad23, a protein involved in nucleotide ...
;
RPS27A
40S ribosomal protein S27a is a protein that in humans is encoded by the ''RPS27A'' gene.
Ubiquitin, a highly conserved protein that has a major role in targeting cellular proteins for degradation by the 26S proteosome, is synthesized as a precurs ...
;
SACS; 8U
SF3A1
Splicing factor 3 subunit 1 is a protein that in humans is encoded by the ''SF3A1'' gene.
This gene encodes subunit 1 of the splicing factor 3a protein complex. The splicing factor 3a heterotrimer includes subunits 1, 2 and 3 and is necessary for ...
;
SUMO1;
SUMO2
Small ubiquitin-related modifier 2 is a protein that in humans is encoded by the ''SUMO2'' gene.
Function
This gene encodes a protein that is a member of the SUMO (small ubiquitin-like modifier) protein family. It is a ubiquitin-like protein an ...
;
SUMO3
Small ubiquitin-related modifier 3 is a protein that in humans is encoded by the ''SUMO3'' gene.
Function
SUMO proteins, such as SUMO3, and ubiquitin (see MIM 191339) posttranslationally modify numerous cellular proteins and affect their metab ...
;
SUMO4;
TMUB1;
TMUB2
Transmembrane and ubiquitin-like domain-containing protein 2 is a protein that in humans is encoded by the ''TMUB2'' gene.
Gene
TMUB2 maps on the human chromosome 17, at locus 17q21.31. TMUB2 sits between two neighboring genes, ASB16-AS1 to t ...
;
UBA52
60S ribosomal protein L40 (RPL40) is a protein that in humans is encoded by the ''UBA52'' gene.
Function
Ubiquitin is a highly conserved nuclear and cytoplasmic protein that has a major role in targeting cellular proteins for protein degradat ...
;
UBB;
UBC
The University of British Columbia (UBC) is a public research university with campuses near Vancouver and in Kelowna, British Columbia. Established in 1908, it is British Columbia's oldest university. The university ranks among the top three ...
;
UBD;
UBFD1;
UBL4A;
UBL4B;
UBL7;
UBLCP1;
UBQLN1;
UBQLN2
Ubiquilin-2 is a protein that in humans is encoded by the ''UBQLN2'' gene.
Function
This gene encodes a ubiquitin-like protein ( ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain ...
;
UBQLN3;
UBQLN4
Ubiquilin 4 is a protein in humans that is encoded by the UBQLN4 gene. Ubiquilin 4 regulates proteasomal protein degradation.
Similarity to Other Proteins
Human UBQLN4 shares a high degree of similarity with related ubiquilins including UBQLN1 ...
;
UBQLNL;
UBTD1;
UBTD2;
UHRF1
Ubiquitin-like, containing PHD and RING finger domains, 1, also known as UHRF1, is a protein which in humans is encoded by the ''UHRF1'' gene.
Function
This gene encodes a member of a subfamily of RING finger domain, RING-finger type E3 ubiqui ...
;
UHRF2;
Related proteins
*
Ubiquitin-associated protein domain
Prediction of ubiquitination
Currently available prediction programs are:
* UbiPred is a
SVM-based prediction server using 31 physicochemical properties for predicting ubiquitination sites.
* UbPred is a
random forest
Random forests or random decision forests is an ensemble learning method for classification, regression and other tasks that operates by constructing a multitude of decision trees at training time. For classification tasks, the output of th ...
-based predictor of potential ubiquitination sites in proteins. It was trained on a combined set of 266 non-redundant experimentally verified ubiquitination sites available from our experiments and from two large-scale proteomics studies.
* CKSAAP_UbSite is SVM-based prediction that employs the composition of k-spaced amino acid pairs surrounding a query site (i.e. any lysine in a query sequence) as input, uses the same dataset as UbPred.
Podcast
* Investigating the ubiquitin proteasome system was the focus of a Dementia Researcher Podcast.
[ ] The podcast was published on 16 August 2021, hosted by Professor Selina Wray from University College London.
See also
*
Autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
*
Autophagin
Autophagin-1 (Atg4/Apg4) is a unique cysteine protease responsible for the cleavage of the carboxyl terminus of Atg8/Apg8/Aut7, a reaction essential for its lipidation during autophagy. Human Atg4 homologues cleave the carboxyl termini of the th ...
*
Endoplasmic-reticulum-associated protein degradation
Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the prote ...
*
JUNQ and IPOD
JUNQ and IPOD are types of cytosolic protein inclusion bodies in eukaryotes.
Neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Huntington's, are associated and correlated with protein aggregation and accumulation of misfolded ...
*
Prokaryotic ubiquitin-like protein
*
SUMO enzymes
SUMO enzymatic cascade catalyzes the dynamic posttranslational modification process of sumoylation (i.e. transfer of SUMO protein to other proteins). The Small Ubiquitin-related Modifier, SUMO-1, is a ubiquitin-like family member that is conju ...
References
External links
GeneReviews/NCBI/NIH/UW entry on Angelman syndromeOMIM entries on Angelman syndromeUniProt entry for ubiquitin* Notes from MIT course.
*
{{Authority control
Proteins
Post-translational modification
Protein structure