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▲ FIGURE 11-22 Interaction of homodimeric leucine-zipper and basic helix-loop-helix (bHLH) proteins with DNA. (a) In leucine-zipper proteins, basic residues in the extended a-helical regions of the monomers interact with the DNA backbone at adjacent major grooves. The coiled-coil dimerization domain is stabilized by hydrophobic interactions between the monomers. (b) In bHLH proteins, the DNA-binding helices at the bottom (N-termini of the monomers) are separated by nonhelical loops from a leucine-zipper-like region containing a coiled-coil dimerization domain. [Part (a) see T E. Ellenberger et al., 1992, Cell 71:1223; part (b) see A. R. Ferre-DAmare et al., 1993, Nature 363:38.]

jacent major grooves separated by about half a turn of the double helix (Figure 11-22a). The portions of the a helices contacting the DNA include positively charged (basic) residues that interact with phosphates in the DNA backbone and additional residues that interact with specific bases in the major groove.

GCN4 forms dimers via hydrophobic interactions between the C-terminal regions of the a helices, forming a coiled-coil structure. This structure is common in proteins containing amphipathic a helices in which hydrophobic amino acid residues are regularly spaced alternately three or four positions apart in the sequence, forming a stripe down one side of the a helix. These hydrophobic stripes make up the interacting surfaces between the a-helical monomers in a coiled-coil dimer (see Figure 3-6c).

Although the first leucine-zipper transcription factors to be analyzed contained leucine residues at every seventh position in the dimerization region, additional DNA-binding proteins containing other hydrophobic amino acids in these positions subsequently were identified. Like leucine-zipper proteins, they form dimers containing a C-terminal coiled-coil dimerization region and an N-terminal DNA-binding domain. The term basic zipper (bZip) now is frequently used to refer to all proteins with these common structural features. Many basic-zipper transcription factors are het-erodimers of two different polypeptide chains, each containing one basic-zipper domain.

Basic Helix-Loop-Helix (bHLH) Proteins The DNA-binding domain of another class of dimeric transcription factors contains a structural motif very similar to the basic-zipper motif except that a nonhelical loop of the polypeptide chain separates two a-helical regions in each monomer (Figure 11-22b). Termed a basic helix-loop-helix (bHLH), this motif was predicted from the amino acid sequences of these proteins, which contain an N-terminal a helix with basic residues that interact with DNA, a middle loop region, and a C-terminal region with hydrophobic amino acids spaced at intervals characteristic of an amphipathic a helix. As with basic-zipper proteins, different bHLH proteins can form heterodimers.

Transcription-Factor Interactions Increase Gene-Control Options

Two types of DNA-binding proteins discussed in the previous section—basic-zipper proteins and bHLH proteins— often exist in alternative heterodimeric combinations of monomers. Other classes of transcription factors not discussed here also form heterodimeric proteins. In some het-erodimeric transcription factors, each monomer has a DNA-binding domain with equivalent sequence specificity. In these proteins, the formation of alternative heterodimers does not influence DNA-binding specificity, but rather allows the activation domains associated with each monomer to be brought together in alternative combinations in a single transcription factor. As we shall see later, and in subsequent chapters, the activities of individual transcription factors can be regulated by multiple mechanisms. Consequently, a single bZIP or bHLH DNA regulatory element in the control region of a gene may elicit different transcriptional responses depending on which bZIP or bHLH monomers that bind to that site are expressed in a particular cell at a particular time and how their activities are regulated.

In some heterodimeric transcription factors, however, each monomer has a different DNA-binding specificity. The resulting combinatorial possibilities increase the number of potential DNA sequences that a family of transcription factors can bind. Three different factor monomers theoretically could combine to form six homo- and heterodimeric factors, as illustrated in Figure 11-23a. Four different factor monomers could form a total of 10 dimeric factors; five monomers, 16 dimeric factors; and so forth. In addition, inhibitory factors are known that bind to some basic-zipper and bHLH monomers, thereby blocking their binding to DNA. When these inhibitory factors are expressed, they repress transcriptional activation by the factors with which they interact (Figure 11-23b). The rules governing the interactions of members of a heterodimeric transcription-factor class are complex. This combinatorial complexity expands both the number of DNA sites from which these factors can activate transcription and the ways in which they can be regulated.

Similar combinatorial transcriptional regulation is achieved through the interaction of structurally unrelated

► FIGURE 11-23 Combinatorial possibilities due to formation of heterodimeric transcription factors.

(a) In the hypothetical example shown, transcription factors A, B, and C can all interact with one another, permitting the three factors to bind to six different DNA sequences (sites 1-6) and creating six combinations of activation domains. Each composite binding site is divided into two half-sites, and each heterodimeric factor contains the activation domains of its two constituent monomers. (b) Expression of an inhibitory factor (green) that interacts only with factor A inhibits binding; hence, transcriptional activation at sites 1, 4, and 5 is inhibited, but activation at sites 2, 3, and 6 is unaffected.

Factor Factor Factor ABC

Activation domain

DNA-binding domain

Inhibitory factor m/

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