Leucine zipper

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"Overhead view", or helical wheel diagram, of a leucine zipper, where d represents leucine, arranged with other amino acids on two parallel alpha helices. Coiledcoil-wheelcartoon.png
"Overhead view", or helical wheel diagram, of a leucine zipper, where d represents leucine, arranged with other amino acids on two parallel alpha helices.

A leucine zipper (or leucine scissors [1] ) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 [2] when they found that an enhancer binding protein had a very characteristic 30-amino acid segment and the display of these amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine 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 chains from one alpha helix interdigitate with those from the alpha helix of a second polypeptide, facilitating dimerization.

Contents

Leucine zippers are a dimerization motif of the bZIP (Basic-region leucine zipper) class of eukaryotic transcription factors. [3] The bZIP domain is 60 to 80 amino acids in length with a highly conserved DNA binding basic region and a more diversified leucine zipper dimerization region. [4] 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 interactions. [5]

Sequence and structure

Another DNA binding domain, the Helix-loop-helix (HLH) dimer, is shown bound to DNA fragment -- each alpha helix represents a monomer. Bzip wikimedia modified.tif
Another DNA binding domain, the Helix-loop-helix (HLH) dimer, is shown bound to DNA fragment — each alpha helix represents a monomer.

Leucine zipper is created by the dimerization of two specific alpha helix monomers bound to DNA. The leucine zipper is formed by amphipathic 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 side of the helix forms a dimer with itself or another similar helix, burying the non-polar amino acids away from the solvent. The hydrophilic side of the helix interacts with the water in the solvent.

Leucine zipper motifs are considered a subtype of coiled coils, which are built by two or more alpha helices that are wound around each other to form a supercoil. 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 repeats in which the amino acids are designated from a’ to g’. [6] 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, [7] residues in positions e and g are charged residues contributing to the electrostatic interaction. [8]

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. [9]

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 may alter the organization of coiled coils and play a role in the formation of leucine zipper heterodimer. [10]

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 lysines and arginines. These basic residues interact in the major groove 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. [2] [4] [11] The bZIP heterodimers exist in a variety of eukaryotes and are more common in organisms with higher evolution complexity. [12] Heterodimeric bZIP proteins differ from homodimeric bZIP and from each other in protein-protein interaction affinity. [13] 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. [13]

A small number of bZIP factors such as OsOBF1 can also recognize palindromic sequences. [14] 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. [14] [15]

Biology

Leucine zipper regulatory proteins include c-fos and c-jun (the AP1 transcription factor), important regulators of normal development, [16] as well as myc family members including myc, max, and mxd1. If they are overproduced or mutated in a vital area, they may cause cancer. [16]

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 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 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) and represses pro-apoptotic genes such as Tumor necrosis factor ligand superfamily member 10 (TRAIL) 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) 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), 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 and vital for the development and function of other immune cells, including but not limited to anti-inflammatory response in helper T cells, production of IgE from B cells, maturation of CD8a dendritic cells and priming of CD8+ T cells. [17]

Related Research Articles

<span class="mw-page-title-main">Alpha helix</span> Type of secondary structure of proteins

An alpha helix is a sequence of amino acids in a protein that are twisted into a coil.

The histone fold is a structural motif located near the C-terminus of histone proteins, characterized by three alpha helices separated by two loops. This motif facilitates the formation of heterodimers, which subsequently assemble into a histone octamer, playing a crucial role in the packaging of DNA into nucleosomes within chromatin. This fold is an ancient and highly conserved structural motif, essential for DNA compaction and regulation across a wide range of species.

A coiled coil is a structural motif in proteins in which 2–7 alpha-helices are coiled together like the strands of a rope. They have been found in roughly 5-10% of proteins and have a variety of functions. They are one of the most widespread motifs found in protein-protein interactions. To aid protein study, several tools have been developed to predict coiled-coils in protein structures. Many coiled coil-type proteins are involved in important biological functions, such as the regulation of gene expression — e.g., transcription factors. Notable examples are the oncoproteins c-Fos and c-Jun, as well as the muscle protein tropomyosin.

<span class="mw-page-title-main">Helix-turn-helix</span> Structural motif capable of binding DNA

Helix-turn-helix is a DNA-binding domain (DBD). The helix-turn-helix (HTH) is a major structural motif capable of binding DNA. Each monomer incorporates two α helices, joined by a short strand of amino acids, that bind to the major groove of DNA. The HTH motif occurs in many proteins that regulate gene expression. It should not be confused with the helix–loop–helix motif.

In molecular biology, a CCAAT box is a distinct pattern of nucleotides with GGCCAATCT consensus sequence that occur upstream by 60–100 bases to the initial transcription site. The CAAT box signals the binding site for the RNA transcription factor, and is typically accompanied by a conserved consensus sequence. It is an invariant DNA sequence at about minus 70 base pairs from the origin of transcription in many eukaryotic promoters. Genes that have this element seem to require it for the gene to be transcribed in sufficient quantities. It is frequently absent from genes that encode proteins used in virtually all cells. This box along with the GC box is known for binding general transcription factors. Both of these consensus sequences belong to the regulatory promoter. Full gene expression occurs when transcription activator proteins bind to each module within the regulatory promoter. Protein specific binding is required for the CCAAT box activation. These proteins are known as CCAAT box binding proteins/CCAAT box binding factors.

<span class="mw-page-title-main">Basic helix–loop–helix</span> Protein structural motif

A basic helix–loop–helix (bHLH) is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors. The word "basic" does not refer to complexity but to the chemistry of the motif because transcription factors in general contain basic amino acid residues in order to facilitate DNA binding.

A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA. Some DNA-binding domains may also include nucleic acids in their folded structure.

<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

<span class="mw-page-title-main">CCAAT-enhancer-binding proteins</span> Protein family

CCAAT-enhancer-binding proteins is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C/EBPs can recruit so-called co-activators that in turn can open up chromatin structure or recruit basal transcription factors.

<span class="mw-page-title-main">Helical wheel</span> Protein structure visual representation

A helical wheel is a type of plot or visual representation used to illustrate the properties of alpha helices in proteins.

<span class="mw-page-title-main">AP-1 transcription factor</span> Instance of defined set in Homo sapiens with Reactome ID (R-HSA-6806560)

Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular processes including differentiation, proliferation, and apoptosis. The structure of AP-1 is a heterodimer composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families.

<span class="mw-page-title-main">Jun dimerization protein</span> Protein-coding gene in the species Homo sapiens

Jun dimerization protein 2 (JUNDM2) is a protein that in humans is encoded by the JDP2 gene. The Jun dimerization protein is a member of the AP-1 family of transcription factors.

<i>HLF</i> (gene) Protein-coding gene in the species Homo sapiens

Hepatic leukemia factor is a protein that in humans is encoded by the HLF gene.

<span class="mw-page-title-main">MAFG</span> Protein-coding gene in the species Homo sapiens

Transcription factor MafG is a bZip Maf transcription factor protein that in humans is encoded by the MAFG gene.

<span class="mw-page-title-main">CEBPG</span> Protein-coding gene in the species Homo sapiens

CCAAT/enhancer-binding protein gamma (C/EBPγ) is a protein that in humans is encoded by the CEBPG gene. This gene has no introns.

<span class="mw-page-title-main">TEF (gene)</span> Protein-coding gene in the species Homo sapiens

Thyrotroph embryonic factor is a protein that in humans is encoded by the TEF gene.

<span class="mw-page-title-main">MAFK</span> Protein-coding gene in the species Homo sapiens

Transcription factor MafK is a bZip Maf transcription factor protein that in humans is encoded by the MAFK gene.

bZIP domain Protein domain

The Basic Leucine Zipper 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 together (dimerize) two DNA binding regions. The DNA binding region comprises a number of basic amino acids such as arginine and lysine. Proteins containing this domain are transcription factors.

Small Maf proteins are basic region leucine zipper-type transcription factors that can bind to DNA and regulate gene regulation. There are three small Maf (sMaf) proteins, namely MafF, MafG, and MafK, in vertebrates. HUGO Gene Nomenclature Committee (HGNC)-approved gene names of MAFF, MAFG and MAFK are “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog F, G, and K”, respectively.

<span class="mw-page-title-main">TEDDM1</span> Protein-coding gene in the species Homo sapiens

Transmembrane epididymal protein 1 is a transmembrane protein encoded by the TEDDM1 gene. TEDDM1 is also commonly known as TMEM45C and encodes 273 amino acids that contains six alpha-helix transmembrane regions. The protein contains a 118 amino acid length family of unknown function. While the exact function of TEDDM1 is not understood, it is predicted to be an integral component of the plasma membrane.

References

  1. ↑ Glick DM (1997). Glossary of Biochemistry and Molecular Biology . Portland Press. ISBN   978-1-85578-088-0. "hair cutting scissors"
  2. 1 2 Landschulz WH, Johnson PF, McKnight SL (June 1988). "The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins". Science. 240 (4860): 1759–64. Bibcode:1988Sci...240.1759L. doi:10.1126/science.3289117. PMID   3289117. S2CID   42512.
  3. ↑ Vinson CR, Sigler PB, McKnight SL (November 1989). "Scissors-grip model for DNA recognition by a family of leucine zipper proteins". Science. 246 (4932): 911–6. Bibcode:1989Sci...246..911V. doi:10.1126/science.2683088. PMID   2683088.
  4. 1 2 E ZG, Zhang YP, Zhou JH, Wang L (April 2014). "Mini review roles of the bZIP gene family in rice". Genetics and Molecular Research. 13 (2): 3025–36. doi: 10.4238/2014.April.16.11 . PMID   24782137.
  5. ↑ Hakoshima, T. (2005). "Leucine Zippers". Encyclopedia of Life Sciences. doi:10.1038/npg.els.0005049. ISBN   0470016175.
  6. ↑ Hodges RS, Sodek J, Smillie LB, Jurasek L (1973). "Tropomyosin: Amino Acid Sequence and Coiled-Coil Structure". Cold Spring Harbor Symposia on Quantitative Biology. 37: 299–310. doi:10.1101/SQB.1973.037.01.040. ISSN   0091-7451.
  7. ↑ Crick FH (September 1953). "The packing of α-helices: simple coiled-coils". Acta Crystallographica. 10 (6 (8-9)): 689–97. doi: 10.1107/s0365110x53001964 .
  8. ↑ Mason JM, Arndt KM (February 2004). "Coiled coil domains: stability, specificity, and biological implications". ChemBioChem. 5 (2): 170–6. doi:10.1002/cbic.200300781. PMID   14760737. S2CID   39252601.
  9. ↑ Krylov D, Vinson CR (2001). "Leucine Zipper". Encyclopedia of Life Sciences. doi:10.1038/npg.els.0003001. ISBN   0470016175.
  10. ↑ Deng Y, Liu J, Zheng Q, Li Q, Kallenbach NR, Lu M (September 2008). "A heterospecific leucine zipper tetramer". Chemistry & Biology. 15 (9): 908–19. doi: 10.1016/j.chembiol.2008.07.008 . PMC   7111190 . PMID   18804028.
  11. ↑ Nijhawan A, Jain M, Tyagi AK, Khurana JP (February 2008). "Genomic survey and gene expression analysis of the basic leucine zipper transcription factor family in rice". Plant Physiology. 146 (2): 333–50. doi:10.1104/pp.107.112821. PMC   2245831 . PMID   18065552.
  12. ↑ Reinke AW, Baek J, Ashenberg O, Keating AE (May 2013). "Networks of bZIP protein-protein interactions diversified over a billion years of evolution". Science. 340 (6133): 730–4. Bibcode:2013Sci...340..730R. doi:10.1126/science.1233465. PMC   4115154 . PMID   23661758.
  13. 1 2 Rodríguez-Martínez JA, Reinke AW, Bhimsaria D, Keating AE, Ansari AZ (February 2017). "Combinatorial bZIP dimers display complex DNA-binding specificity landscapes". eLife. 6: e19272. doi: 10.7554/eLife.19272 . PMC   5349851 . PMID   28186491.
  14. 1 2 Shimizu H, Sato K, Berberich T, Miyazaki A, Ozaki R, Imai R, Kusano T (October 2005). "LIP19, a basic region leucine zipper protein, is a Fos-like molecular switch in the cold signaling of rice plants". Plant & Cell Physiology. 46 (10): 1623–34. doi: 10.1093/pcp/pci178 . PMID   16051676.
  15. ↑ Nantel A, Quatrano RS (December 1996). "Characterization of three rice basic/leucine zipper factors, including two inhibitors of EmBP-1 DNA binding activity". The Journal of Biological Chemistry. 271 (49): 31296–305. doi: 10.1074/jbc.271.49.31296 . PMID   8940135.
  16. 1 2 Curran, Tom; Franza, B.Robert (November 1988). "Fos and jun: The AP-1 connection". Cell. 55 (3): 395–397. doi:10.1016/0092-8674(88)90024-4. ISSN   0092-8674. PMID   3141060. S2CID   5068895.
  17. ↑ Keniry, Megan; Dearth, Robert K.; Persans, Michael; Parsons, Ramon (2014-06-30). "New Frontiers for the NFIL3 bZIP Transcription Factor in Cancer, Metabolism and Beyond". Discoveries. 2 (2): e15. doi:10.15190/d.2014.7. PMC   4629104 . PMID   26539561.
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