Leucine-zipper motif

The leucine zipper motif (see Chapter 3) was first recognized in the amino acid sequences of a yeast transcription factor GCN4, the mammalian transcription factor C/EBP, and three oncogene products, Fos, Jun and Myc, which also act as transcription factors. When the sequences of these proteins are plotted on a helical wheel, a remarkable pattern of leucine residues... 

The coiled-coil structure of the leucine zipper motif is not the only way that homodimers and heterodimers of transcription factors are formed. As we saw in Chapter 3 when discussing the RNA-binding protein ROP, the formation of a four-helix bundle structure is also a way to achieve dimerization, and the helix-loop-helix (HLH) family of transcription factors dimerize in this manner. In these proteins, the helix-loop-helix region is preceded by a sequence of basic amino acids that provide the DNA-binding site (Figure 10.23), and... 

The cAMP responsive element binding factor (CREB) is also activated by phosphorylation. Depending on the stimuli, CREB is the target of a cAMP dependent protein kinase or of kinases called MAPKs, RSK, and CamKIV. As in AP-1, CREB carries a basic leucine zipper motif (bZDP), which mediates homo dimerization of CREB when bound to the CRE. 

The leucine zipper motif was recently successfully employed for the construction of native-like triple-stranded coiled-coil in solution [29]. 

Proteins with the helix-turn-helix or leucine zipper motifs form symmetric dimers, and their respective DNA binding sites are symmetric palindromes. In proteins with the zinc finger motif, the binding site is repeated two to nine times. These features allow for cooperative interactions between binding sites and enhance the degree and affinity of binding. 

Figure 39-15. The leucine zipper motif. A shows a helical wheel analysis of a carboxyl terminal portion of the DNA binding protein C/EBP. The amino acid sequence is displayed end-to-end down the axis of a schematic a-helix. The helical wheel consists of seven spokes that correspond to the seven amino acids that comprise every two turns of the a-helix. Note that leucine residues (L) occur at every seventh position. Other proteins with "leucine zippers" have a similar helical wheel pattern. B is a schematic model of the DNA binding domain of C/EBP. Two identical C/EBP polypeptide chains are held in dimer formation by the leucine zipper domain of each polypeptide (denoted by the rectangles and attached ovals). This association is apparently required to hold the DNA binding domains of each polypeptide (the shaded rectangles) in the proper conformation for DNA binding. (Courtesy ofS McKnight)...

Tadokoro, S., Tachibana, T., Imanaka, T Nishida, W and Sobue, K. (1999) Involvement of unique leucine-zipper motif of PSD-Zip45 (Homer lc/vesl-lL) in group 1 metabotropic glutamate receptor clustering. Proc. Natl. Acad. Sci. USA 96, 13801-13806. 

The leucine zipper itself does not participate in the recognition it is only utilized for dimerization of the proteins. The N-terminal end of the basic leucine zipper motif is relatively unstructured in the absence of DNA. A helical structure is induced upon binding to DNA allowing specific contacts to the recognition sequence. Dimer formation is a prerequisite for the exact positioning of the N-terminal basic end in the major groove of the DNA. Analogous to the dimeric structure of the protein, the DNA sequence displays 2-fold synunetry (see 1.2.4). 

Fig. 1.7. Basic leudne zipper and heltx-loop-heltx motif in complex with DNA. A) The basic leucine zipper of the transcription activator GCN4 of yeast consists of two slightly curved a-hehces, which dimerize with the help of the leucine zipper motif. The sequence specific binding of DNA occurs via the basic ends of the two helices. They insert themselves into the major groove of the DNA. B) The helix-loop-helix motif of the eucaryotic transcription factor Max complexed with DNA. Molscript drawing (Kraulis 1991).

Struhl, K., Helix-tum-helix, zinc-finger and leucine-zipper motifs for eukaryotic transcriptional regulatory proteins. 

Li W, Jain MR, Chen C, Yue X, Hebbar Y, Zhou R, Kong AN. 2005. Nrf2 Possesses a redox-insensitive nuclear export signal overlapping with the leucine zipper motif. J Biol Chem 280 28430-28438. 

Schmidt, R.J., Burr, F.A., Aukerman, M.J. Burr, B. (1990). Maize regulatory gene opaque-2 encodes a protein with a leucine-zipper motif that binds to zein DNA. Proceedings of the National Academy of Sciences (USA) 87, 46-50. 

Tabata, T., Takase, H., Takayama, S., Mikami, K., Nakatsuka, A., Kawata, T., Nakayama, T. Iwabuchi, M. (1989). A protein that binds to a cw-acting element of wheat histone genes has a leucine zipper motif. Science 245, 965-9. 

A leucine zipper has a leucine every seventh amino acid and forms an a-helix with the leucines presented on the same side of the helix every second turn, giving a hydrophobic surface. Two transcription factor monomers can interact via the hydrophobic faces of their leucine zipper motifs to form a dimer. The helix-loop-helix (HLH) motif contains two a-helices separated by a nonhelical loop. The C-terminal a-helix has a hydrophobic face two transcription factor monomers, each with an HLH motif, can dimerize by interaction between the hydrophobic faces of the two C-terminal a-helices. 

Evolutionary changes in the amino acid sequence of leucine (or hybrid) leucine zipper motifs in the CCD of dysbindin-1 orthologs. The amino acid (aa) numbers specify the beginning and end of the zipper motif in each species. These motifs consist of 28 amino acids broken into four sets of 7 aa sequences (i.e., four heptads). Attention is called to the amino acids in the 6" position within each heptad, the identity of which is especially important to the stability of interactions with leucine zippers on other protein molecules... 

Further discussion of the dysbindin family is limited to dysbindin-1 since little is known about other family members apart from the fact that dysbindin-2B is a casein kinase 1 binding partner and a stem cell factor apoptosis response protein. In contrast, much has been learned about dysbindin-1 since its discovery was reported by Benson et al. (2001). It is the only member of the dysbindin family known to exist in invertebrates, specifically the fruit fly, and may thus date back 600 million years. Unlike all other dysbindin paralogs, it contains a coiled coil domain (CCD) allowing extensive interactions with other proteins. A leucine zipper motif in the CCD changed in the course of evolution in a manner permitting more durable interactions with binding partners. 

Richie-Jannetta R, Francis SH, Corbin JD. 2003. Dimerization of cgmp-dependent protein kinase I 3 is mediated by an extensive amino-terminal leucine zipper motif, and dimerization modulates enzyme function. J Biol Chem 278 50070-50079. 

Fig. 4. a cDNA sequence of Cop c 1 and deduced amino acid sequence, b Deduced amino acid sequence of rCop c 1 fusion protein. Underlining = N-terminal His-tag italics = amino acid sequence that derives from multicloning site of -ZAPII phagemid SK. bold = sequence encoded by Cop c 1. c The same deduced amino acid sequence is shown twice. Upper sequence two leucine zipper motifs termed N- and C-terminal lower sequence two different repeats, 6 times L-4-L and 7 times P-5-L. 

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