A leucine zipper (or leucine scissors
) is a common three-dimensional
structural motif
In a polymer, chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common Biomolecular structure#Tertiary structure, three-dimensional structure that appears in a variety of different, evolutionarily unrel ...
in proteins. They were first described by Landschulz and collaborators in 1988
when they found that an enhancer
binding protein A binding protein is any protein that acts as an agent to bind two or more molecules together.
Examples include:
* DNA-binding protein
** Single-strand binding protein
** Telomere-binding protein
*RNA-binding protein
** Poly(A)-binding protein
** ...
had a very characteristic 30-amino acid segment and the display of these
amino acid sequence
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...
s on an idealized
alpha helix
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...
revealed a periodic repetition of
leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...
residues at every seventh position over a distance covering eight helical turns. The polypeptide segments containing these periodic arrays of leucine residues were proposed to exist in an alpha-helical conformation and the leucine
side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a l ...
s from one alpha helix interdigitate with those from the alpha helix of a second polypeptide, facilitating dimerization.
Leucine zippers are a dimerization motif of the
bZIP
The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required to hold tog ...
(Basic-region leucine zipper) class 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 ...
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s.
The bZIP domain is 60 to 80
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 in length with a highly conserved
DNA binding basic region and a more diversified leucine zipper dimerization region.
The localization of the leucines are critical for the DNA binding to the proteins. Leucine zippers are present in both eukaryotic and prokaryotic regulatory proteins, but are mainly a feature of eukaryotes.
They can also be annotated simply as ZIPs, and ZIP-like motifs have been found in proteins other than transcription factors and are thought to be one of the general protein modules for
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.
Sequence and structure
Leucine zipper is created by the
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
ization of two specific alpha helix
monomer
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
s bound to DNA. The leucine zipper is formed by
amphipathic
An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...
interaction between two ZIP domains. The ZIP domain is found in the alpha-helix of each monomer, and contains leucines, or leucine-like amino acids. These amino acids are spaced out in each region's polypeptide sequence in such a way that when the sequence is coiled in a 3D alpha-helix, the leucine residues line up on the same side of the helix. This region of the alpha-helix- containing the leucines which line up- is called a ZIP domain, and leucines from each ZIP domain can weakly interact with leucines from other ZIP domains, reversibly holding their alpha-helices together (dimerization). When these alpha helices dimerize, the zipper is formed. The
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
side of the helix forms a dimer with itself or another similar helix, burying the non-polar amino acids away from the
solvent
A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
. The
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are no ...
side of the helix interacts with the water in the solvent.
Leucine zipper motifs are considered a subtype of
coiled coil
A coiled coil is a structural motif in proteins in which 2–7
alpha-helices are coiled together like the strands of a rope. (Dimers and trimers are the most common types.) Many coiled coil-type proteins are involved in important biological fun ...
s, which are built by two or more alpha helices that are wound around each other to form a
supercoil
DNA supercoiling refers to the amount of twist in a particular DNA strand, which determines the amount of strain on it. A given strand may be "positively supercoiled" or "negatively supercoiled" (more or less tightly wound). The amount of a st ...
. Coiled coils contain 3- and 4-residue repeats whose hydrophobicity pattern and residue composition is compatible with the structure of amphipathic alpha-helices. The alternating three- and four-residue sequence elements constitute
heptad repeat
The heptad repeat is an example of a structural motif that consists of a repeating pattern of seven amino acids:
''a b c d e f g''
H P P H C P C
where H represents hydrophobic residues, C represents, typically, charged residues, and P repres ...
s in which the amino acids are designated from a’ to g’. While residues in positions a and d are generally hydrophobic and form a zigzag pattern of knobs and holes that interlock with a similar pattern on another strand to form a tight-fitting hydrophobic core, residues in positions e and g are charged residues contributing to the electrostatic interaction.
In the case of leucine zippers, leucines are predominant at the d position of the heptad repeat. These residues pack against each other every second turn of the alpha-helices, and the hydrophobic region between two helices is completed by residues at the a positions, which are also frequently hydrophobic. They are referred to as coiled coils unless they are proven to be important for protein function. If that is the case, then they are annotated in the “domain” subsection, which would be the bZIP domain.
Two different types of such a-helices can pair up to form a heterodimeric leucine zipper. With apolar amino acid residues at either the e or g position, a heterotetramer consisting of 2 different leucine zippers can be generated in-vitro, which implies that the overall hydrophobicity of the interaction surface and
van der Waals interaction
In molecular physics, the van der Waals force is a distance-dependent interaction between atoms or molecules. Unlike ionic or covalent bonds, these attractions do not result from a chemical electronic bond; they are comparatively weak and the ...
may alter the organization of coiled coils and play a role in the formation of leucine zipper heterodimer.
Specific binding between bZIP proteins and DNA
The bZIP interacts with the DNA via basic, amine residues (see basic amino acids in (
provided table (sort by pH)) of certain amino acids in the "basic" domain, such as
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 ...
s and
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
s. These basic residues interact in the
major groove
Major (commandant in certain jurisdictions) is a military rank of commissioned officer status, with corresponding ranks existing in many military forces throughout the world. When used unhyphenated and in conjunction with no other indicators ...
of the DNA, forming sequence-specific interactions. The mechanism of transcriptional regulation by bZIP proteins has been studied in detail. Most bZIP proteins show high binding affinity for the ACGT motifs, which include CACGTG (G box), GACGTC (C box), TACGTA (A box), AACGTT (T box), and a GCN4 motif, namely TGA(G/C)TCA.
The bZIP heterodimers exist in a variety of eukaryotes and are more common in organisms with higher evolution complexity. Heterodimeric bZIP proteins differ from homodimeric bZIP and from each other in protein-protein interaction affinity.
These heterodimers exhibit complex DNA binding
specificity. When combined with a different partner, most of the bZIP pairs bind to DNA sequences that each individual partner prefers. In some cases, dimerization of different bZIP partners can change the DNA sequence that the pair targets in a manner that could not have been predicted based on the preferences of each partner alone. This suggests that, as heterodimers, bZIP transcription factors are able to change their preferences for which location they target in the DNA. The ability of bZIP domain forming dimers with different partners greatly expands the locations on the genome to which bZIP transcription factors can bind and from which they can regulate gene expression.
A small number of bZIP factors such as OsOBF1 can also recognize
palindromic sequence
A palindromic sequence is a nucleic acid sequence in a double-stranded DNA or RNA molecule whereby reading in a certain direction (e.g. 5' to 3') on one strand is identical to the sequence in the same direction (e.g. 5' to 3') on the complemen ...
s.
However, the others, including LIP19, OsZIP-2a, and OsZIP-2b, do not bind to DNA sequences. Instead, these bZIP proteins form heterodimers with other bZIPs to regulate
transcriptional activities.
Biology
Leucine zipper regulatory proteins include
c-fos
Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkin ...
and
c-jun
Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only lat ...
(the AP1 transcription factor), important regulators of normal development,
as well as myc family members including
myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...
,
max, and
mxd1
MAD protein is a protein that in humans is encoded by the ''MXD1'' gene.
MAD-MAX dimerization protein belongs to a subfamily of MAX-interacting proteins. This protein competes with MYC for binding to MAX to form a sequence-specific DNA-binding c ...
. If they are overproduced or mutated in a vital area, they may cause
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 ...
.
BZIP containing transcription factors regulate various biological processes
The bZIP-containing Nuclear factor interleukin 3 regulated protein (
NFIL3) is a transcription repressor which play multiple roles in regulating various biological processes. The NFIL3 protein has 462 amino acids including a b-ZIP domain . The N-terminal portion of the domain contains the basic motif, which directly binds to DNA. The C-terminal portion of the b-ZIP domain contains an amphipathic leucine zipper region, which mediates homo- and hetero- dimerization.
The expression of the ''Nfil3'' gene changes along with the
circadian cycle
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
and the NFIL3, as a repression factor, regulates circadian rhythm. NFIL3 competes with the transcription activator D site albumin promoter binding protein (
DBP) in binding with the D box elements in the DNA, which is one of the circadian transcription factor consensus sites. DBP is another bZIP protein and shows an opposite portfolio of expression level to that of NFIL3. When NFIL3 level is high, genes under control of the D box elements will be repressed. Overexpression of ''Nfil3'' shortens the circadian cycle.
NFIL3 influences cell survival and involves in oncogenesis. NFIL3 is shown to be a survival factor that hinders
apoptotic
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 includ ...
cell death in numerous cell types and leads to oncogenesis. High expression level of NFIL3 is shown associate with breast cancer. In cancer cells, NFIL3 associates with Histone deacetylase2 (
HDAC2
Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the ''HDAC2'' gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the co ...
) and represses pro-apoptotic genes such as Tumor necrosis factor ligand superfamily member 10 (
TRAIL
A trail, also known as a path or track, is an unpaved lane or small road usually passing through a natural area. In the United Kingdom and the Republic of Ireland, a path or footpath is the preferred term for a pedestrian or hiking trail. Th ...
) and TNF receptor superfamily member 6 (FAS) to prevent apoptosis. NFIL3 can also hinder apoptosis in cancer cells by binding to DNA and block the access of transcription factor Forkhead box O1 (
FOXO1
Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...
) to cell death genes, which undermines cell cycle and promotes oncogenesis. In colon cancer, NFIL3 may also block the recruitment of another type of transcription factors, Proline Acid Rich (PAR) proteins.
NFIL3 functions as a repressor to neuron regeneration associated genes. ''Nfil3'' is expressed in neuron cells with regeneration potential to keep cell growth under control. Expression of ''Nfil3'' is induced by phosphorylated cAMP-response element binding protein (
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
), and the NFIL3 protein in turn competes for binding sites shared with CREB and CCAAT/Enhancer Binding Protein (
CEBP), which downregulates target genes of CREB and CEBP to counteract the effect of cAMP signaling. Meanwhile, NFIL3 binds to its own promoter to repress its own expression, creating a negative feedback regulation of neuron regeneration.
NFIL3 is also found to be important in immunology. It is required for
natural killer cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
and vital for the development and function of other immune cells, including but not limited to anti-inflammatory response in
helper T cells
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
, production of IgE from B cells, maturation of CD8a dendritic cells and priming of CD8+ T cells.
References
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External links
*
{{Transcription factors, g1
Protein structural motifs
DNA-binding substances
de:Leucin-Zipper