Transcription factors dimerization domains

While the regulation of transcription via protein-DNA interaction inhibitors holds promise for the future due to the predictable structure of the target DNA domains, it still suffers from many challenges. Thus, efforts are currently more focused on the inhibition of transcription factor dimerization and the targeting of DNA-binding domains on transcription factors. 

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.

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. 

Sequence-specific transcription factors often bind as multimers especially as dimers to DNA. This allows binding of mirror-imaged sequences (palindromes) in the DNA that are separated by a few spacer nucleotides. The dimerization is stabilized by hydrophobic motifs within dimerization motifs of each transcription factor molecule. Dependent on the nature of the dimerization domain and the abundance of individual transcription factors homo- or heterodimers can form and bind to palindromes with differential activity. 

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. 

Family of transcription factors that modulate the expression of genes which control immune, inflammatory, and acute-phase responses, as well as cell growth, responses to stress, apoptosis, and oncogenesis. All members of this family have a Rel-homology domain that contains sequences responsible for dimerization and DNA binding. In vertebrates, this family includes NF-kB1 (also known as p50), NF-kB2 (also known as p52), Rel (also known as cRel), Rel-A (also known as p65), and Rel-B. 

It is believed that many transcription factors bind DNA as dimers ( dimeric transcription factors) in either the same or opposite orientation. The DNA sites therefore can look like two direct repeat sequences or like palindromes. The interaction of the subunits with each other must obviously be specific and be mediated by dimerization domains. Specificity and stability of the dimers (dimeric transcription factors) is mostly promoted by hydrophobic or ionic inteiphases, e.g. a... 

FIGURE 8.12 Direct phosphorylation of the STAT class of transcription factors. Through their SH2 domains, the p84Slalla and p91StaIlb associate with the receptor and become phosphorylated on tyrosine residues. They form a dimer (called the Sis-inducible factor, or SIF) that translocates to the nucleus, where it binds to a Sis-inducible element (SIE) and activates transcription of, for example, the c-fos gene. 

Figure I. The hetero dimeric Core Binding Factor (CBF) transcription factor is comprised of one of three RUNX family proteins (a snbnnit) and a b-subimit, which is encoded by a single gene. The RUNX proteins contain two conserved and functional domains the runt homology domain (RHD) and the transcription activation domain (TAD). Interactions between the RHD and the hetero dimerization domain (HD) of CBFb are essential for most of the known activities of CBF. Synerigistic activity with a number of different transcription factors is well established.

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-... 

Figure 5-40 Structure of a protein known as transcription factor NF-kB bound to its DNA target. Each subunit of the dimeric protein contains two (3 barrel domains. The loops at the ends of the barrels interact with the DNA in the center. From Muller et al.433 Courtesy of Stephen C. Harrison.

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