Transcription factors basic domains

Figure 10.23 Domain arrangement along the polypeptide chains of three families of transcription factors b/z, b/HLH and b/HLH/z. All three have a basic region (blue) that binds DNA. Dimerization is achieved by the zipper region (purple) in the b/z family, by the Hl-loop-H2 region (red-yellow-green) in the b/HLH family and by a combination of both the zipper and the HLH regions in the b/HLH/z family.

Figure 10.24 Structure of a monomer of the DNA-binding domain of the transcription factor MyoD. The domain, which belongs to the b/HLH family, comprises two a helices joined by a loop region. The basic region (blue) and the first helix HI (red) of the helix-loop-helLx region form one continous a helix. (Adapted from P.C.M. Ma et al.. Cell 77 451-459, 1994.)...

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. 

A leucine zipper is a structural motif present in a large class of transcription factors. These dimeric proteins contain two extended alpha helices that grip the DNA molecule much like a pair of scissors at adjacent major grooves. The coiled-coil dimerization domain contains precisely spaced leucine residues which are required for the interaction of the two monomers. Some DNA-binding proteins with this general motif contain other hydrophobic amino acids in these positions hence, this structural motif is generally called a basic zipper. 

Histone methylation participates in the regulation of gene expression patterns. Unlike histone acetylation, histone methylation does not alter the charge of the amino acid and hence the histone tail. There are changes in the basicity and the hydrophobicity which are relatively small when viewed at the scale of the histone but still influence the affinity of the histone tails to certain proteins, for example transcription factors, which in turn result in certain signaling events. The histone methyltransferases are usually subdivided into three classes SET domain lysine methyltransfeases, nonSET domain lysine methyltransferases and arginine methyltransferases (PRMTs). All of them utilize S-adenosylmethionine (SAM) as cosubstrate for the methylation reaction... 

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). 

A variation on the basic theme of receptor Tyr kinases is seen in receptors that have no intrinsic protein kinase activity but, when occupied by their ligand, bind a soluble Tyr kinase. One example is the system that regulates the formation of erythrocytes in mammals. The cytokine (developmental signal) for this system is erythropoietin (EPO), a 165 amino acid protein produced in the kidneys. When EPO binds to its plasma membrane receptor (Fig. 12-9), the receptor dimerizes and can now bind the soluble protein kinase JAK (Janus kinase). This binding activates JAK, which phosphory-lates several Tyr residues in the cytoplasmic domain of the EPO receptor. A family of transcription factors, collectively called STATs (signal transducers and activators of transcription), are also targets of the JAK kinase activity. An SH2 domain in STATS binds (P)-Tyr residues in the EPO receptor, positioning it for this phosphorylation by JAK. When STATS is phosphorylated in re-... 

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. 

The helix-loop-helix (HLH) dimerization domain is quite distinct from the helix-turn-helix motif described above (which is involved in DNA binding not dimerization) and must not be confused with it. The HLH domain consists of two a-helices separated by a nonhelical loop. The C-terminal a-helix has hydrophobic amino acids on one face. Thus two transcription factor monomers, each with an HLH motif, can dimerize by interaction between the hydrophobic faces of the two C-terminal a-helices. Like the leucine zipper (see above), the HLH motif is often found in transcription factors that contain basic DNA binding domains. Again, like the leucine zipper, the HLH motif can dimerize transcription factor monomers to form either homodimers or heterodimers. This ability to form heterodimers markedly increases the variety of active transcription factors that are possible and so increases the potential for gene regulation. 

These receptors are chiefly responsible for the physiological effects of steroid hormones such as cortisol as well as thyroid hormone and vitamin A. They are proteins that share a common basic structure consisting of a ligand binding domain and a DNA binding domain (comprised of zinc finger motifs). They operate as ligand-responsive transcription factors (see Chap. 17 for further discussion). 

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. 

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