Basic leucine zipper

Activator Protein-1 (API) comprises transcriptional complexes formed by dimers of members oftheFos, Jun, and ATF family of transcription factors. These proteins contain basic leucine zipper domains that mediate DNA binding and dimerization. They regulate many aspects of cell physiology in response to environmental changes. 

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. 

Our laboratory started to work on circadian rhythms by serendipity, while studying the liver-specific transcription of the serum albumin gene. We isolated a cDN A copy for a transcription factor that we dubbed DBP (for albumin promoter D-element Binding Protein). DBP, a basic leucine zipper (bZip) transcription factor, is the founding member of the PAR (proline-acidic amino acid rich)-domain bZip transcription factors, a small subfamily of bZip proteins consisting of DBP, TEF and HLF. It turned out that DBP protein and mRNA accumulation undergo circadian cycles with amplitudes in excess of one hundred-fold (Wuarin Schibler 1990). 

Basic Leucine Zipper and Helix-Loop-Helix Motifs... 

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).

Ma Q, Kinneer K, Bi Y, Chan JY, Kan YW. Induction of murine NAD(P)H quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap n collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. Biochem J 2004 377 205-213. 

DNA binding domains called basic domains (rich in basic amino acids), occur in transcription factors in combination with leucine zipper or helix-loop-helix (HLH) dimerization domains (see below). The combination of basic domain and dimerization domain gives these proteins their names of basic leucine zipper proteins (bZIP) or basic HLH proteins, respectively. In each case the dimerization means that two basic domains (one from each monomer) interact with the target DNA. 

Figure 13.12. The Nrf family and Maf family transcription factors. The basic domain is involved in DNA binding and the leucine zipper domain is a dimerization module with other basic-leucine zipper transcription factors. Small Maf proteins such as MafK and MafG het-erodimerize with Nrf2 for binding and activation of the ARE.

Gachon, F., Olela, F. F., Schaad, O., Descombres, P., and Schibler, U. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab. 4, 25-36, 2006. 

The structure of the heterodimeric transcription factor Fos/Jun bound to DNA has been solved. Jun contains a basic leucine zipper (bZIP) motif. Formation of a stable heterodimer is necessary for binding to DNA (see below). 

M. Kwong, Y. W. Kan, and J. Y. Chan. The CNC basic leucine zipper factor Nrfl, is essential for cell stimulation to oxidative stress-inducing agents. Role for Nrfl in y-glutamylcysteine synthetase expression in mouse fibroblasts. J Biol Chem, 274 (52), 37491—37498, 1999. 

CNC Cap n Collar family of basic leucine zipper proteins... 

Walker A Motif A motif described in SKN-1, a transcription factor in Caenorhabditis ele-gans. See Walker, A.K., See, R., Batchelder, C. et al., A conserved transcription motif suggesting functional parallels between Caenorhabitis ele-gans SKN-1 and Cap n Collar-related basic leucine zipper proteins, J. Biol. Chem. 275, 22166-22171, 2000. 

Studies using knockout mice implicate the basic leucine zipper Nrf2 as part of the transcriptional complex directly involved in mediating ARE-dependent transcriptional... 

McMahon, M., Itoh, K. et al.. The Cap n Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res., 61, 3299-3307, 2001. 

Moi P, Chan K, Asunis I, Cao A, Kan YW. 1994. Isolation of NF-E2 related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the /3-globin locus control region. Proc. Natl. Acad. Sci. USA 91.9926-30... 

Andrews NC, Erdjument-Bromage H, Davidson MB, Temspt P, Orkin SH. 1993. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature 362 722-28... 

Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, et al. 1996. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol. Cell. Biol. 16 6083-95... 

---