Associate Editor(s)-in-Chief: Henry A. Hoff
A leucine zipper, aka leucine scissors, is a super secondary structural motif found in proteins that creates adhesion forces in parallel alpha helices. It is a common dimerization domain found in some proteins involved in regulating gene expression.
The main feature of the leucine zipper domain is the predominance of the common amino acid leucine at the d position of the heptad repeat. Leucine zippers were first identified by sequence alignment of certain transcription factors which identified a common pattern of leucines every seven amino acids. These leucines were later shown to form the hydrophobic core of a coiled coil.
Each half of a leucine zipper consists of a short alpha-helix with a leucine residue at every seventh position. The standard 3.6 residues per turn alpha-helix structure changes slightly to become a 3.5 residues per turn alpha-helix. Known also as the heptat repeat, one leucine comes in direct contact with another leucine on the other strand every second turn.
The bZip family of transcription factors consist of a basic region which interacts with the major groove of a DNA molecule through hydrogen bonding, and a leucine zipper region which is responsible for dimerization.
bZIP DNA binding domains
Leucine zippers are a dimerization motif of the BZIP domain (bZIP) (Basic-region leucine zipper) class of eukaryotic transcription factors. 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. 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.
The bZIP interacts with 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 (Landschulz et al., 1988; Nijhawan et al., 2008)."
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 sequences. 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.
Leucine zipper regulatory proteins include c-fos and c-jun (the AP1 transcription factor), important regulators of normal development. If they are overproduced or mutated in a vital area, they may generate cancer. These proteins interact with the DNA as dimers (homo- or hetero-) and are also called basic zipper proteins (bZips).
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