UBE1
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Ubiquitin-like modifier activating enzyme 1 (UBA1) is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
which in humans is encoded by the ''UBA1''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. UBA1 participates in
ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
and the
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 ...
pathway for
protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduc ...
and
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 ...
, among many other biological processes. This protein has been linked to
X-linked spinal muscular atrophy type 2 X-linked spinal muscular atrophy type 2 (SMAX2, XLSMA), also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of motor neurons in the anterior horn of spinal cord resulting in gene ...
, neurodegenerative diseases, and
cancers 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 bl ...
.


Structure


Gene

The ''UBA1'' gene is located in the
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
band Xp11.23, consisting of 31 exons.


Protein

The UBA1 for
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
(Ub) is a 110–120 kDa monomeric protein, and the UBA1 for the
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 ...
(Ubls) NEDD8 and SUMO are
heterodimeric In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
complexes with similar molecular weights. All
eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, 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 ...
UBA1 contain a two-fold repeat of a
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...
, derived from the bacterial MoeB and ThiF proteins, with one occurrence each in the N-terminal and
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 ...
half of the UBA1 for Ub, or the separate subunits of the UBA1 for NEDD8 and SUMO. The UBA1 for Ub consists of four building blocks: First, the adenylation domains composed of two MoeB/ThiF-homology motifs, the latter of which binds ATP and Ub; second, the catalytic cysteine half-domains, which contain the E1 active site cysteine inserted into each of the adenylation domains; third, a four-
helix A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helic ...
bundle that represents a second insertion in the inactive adenylation domain and immediately follows the first catalytic cysteine half-domain; and fourth, the C-terminal ubiquitin-fold domain, which recruits specific E2s.


Function

The protein encoded by this gene catalyzes the first step in
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
conjugation, or ubiquitination, to mark cellular proteins 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 ...
. Specifically, UBA1 catalyzes the ATP-dependent adenylation of ubiquitin, thereby forming 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 ...
bond between the two. It also continues to participate in subsequent steps of ubiquination as a Ub carrier. There are only two human ubiquitin-activating enzymes, UBA1 and UBA6, and thus UBA1 is largely responsible for protein ubiquitination in humans. Through its central role in ubiquitination, UBA1 has been linked to
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 sub ...
regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation. Additionally, UBA1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during
stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
.


Clinical significance

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s in ''UBA1'' are associated with
X-linked spinal muscular atrophy type 2 X-linked spinal muscular atrophy type 2 (SMAX2, XLSMA), also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of motor neurons in the anterior horn of spinal cord resulting in gene ...
. UBA1 has also been implicated in other neurodegenerative diseases, including spinal muscular atrophy, as well as cancer and tumors. Since UBA1 is involved in multiple biological processes, there are concerns that inhibiting UBA1 would also damage normal cells. Nonetheless, preclinical testing of a UBA1 inhibitor in mice with leukemia revealed no additional toxic effects to normal cells, and the success of other drugs targeting pleiotropic targets likewise support the safety of using UBA1 inhibitor in cancer treatment Moreover, the UBA1 inhibitors Largazole, as well as its ketone and ester derivatives, preferentially targets cancer over normal cells by specifically blocking the ligation of Ub and UBA1 during the adenylation step of the E1 pathway. MLN4924, a NEDD8-activating enzyme inhibitor functioning according to similar mechanisms, is currently undergoing phase I clinical trials. An autoinflammatory condition identified in 2020 and named VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to mutation in methionine41 in UBA1, the E1 enzyme that initiates
ubiquitylation Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fou ...
.


Interactions

UBA1 has been shown to interact with: * UBC13 * PYR-41 * himeic acid A * hyrtioreticulins A–E


References


Further reading

* * * * * * * * * * * * * * * * * * *


External links

* {{Posttranslational modification