Heterodimer

Two protein hormones, inhibin and activin, have been identified in gonadal tissue. Inhibin has been isolated from ovarian foUicular fluid and found to inhibit pituitary secretion of FSH. Inhibin is a glyocoprotein heterodimer consisting of two disulfide-linked subunits, a and P two types of P-subunit,... 

P and Pg, exist in foUicular fluid. Control of inhibin secretion involves a feedback relationship in which circulating FSH stimulates inhibin secretion, which in turn reduces the secretion of FSH (8). Both the homo- and the heterodimers of the P-subunits of inhibin promote the secretion of FSH and thus have been termed activins. Activin is secreted by the ovary and the testes into the circulation. In addition, both inhibin and activin have intragonadal autocrine and paracrine effects that influence gonadal steroidogenesis (9). 

The relationship between the two receptors for NGF is complex and not yet completely understood. It has been suggested that the functional form of the NGF receptor is a heterodimer of p75 and pl40 proteins. BDNF and NT-3 bind to p75, but the functional receptors for these neurotrophins are the proto-oncogene products of and trkQ. 

Figure 9.12 Schematic diagram of the structure of the heterodimeric yeast transcription factor Mat a2-Mat al bound to DNA. Both Mat o2 and Mat al are homeodomains containing the helix-turn-helix motif. The first helix in this motif is colored blue and the second, the recognition helix, is red. (a) The assumed structure of the Mat al homeodomain in the absence of DNA, based on Its sequence similarity to other homeodomains of known structure, (b) The structure of the Mat o2 homeodomain. The C-terminal tail (dotted) is flexible in the monomer and has no defined structure, (c) The structure of the Mat a 1-Mat a2-DNA complex. The C-terminal domain of Mat a2 (yellow) folds into an a helix (4) in the complex and interacts with the first two helices of Mat a2, to form a heterodimer that binds to DNA. (Adapted from B.J. Andrews and M.S. Donoviel, Science 270 251-253, 1995.)...

How is the binding specificity of the heterodimer achieved compared with the specificity of Mat a2 alone The crystal structure rules out the simple model that the contacts made between the Mat a2 homeodomain and DNA are altered as a result of heterodimerization. The contacts between the Mat o2 homeodomain and DNA in the heterodimer complex are virtually indistinguishable from those seen in the structure of the Mat o2 monomer bound to DNA. However, there are at least two significant factors that may account for the increased specificity of the heterodimer. First, the Mat al homeodomain makes significant contacts with the DNA, and the heterodimeric complex will therefore bind more tightly to sites that provide the contacts required by both partners. Second, site-directed mutagenesis experiments have shown that the protein-protein interactions involving the... 

Li, T, et al. Crystal structure of the MATal/MATa2 home-odomain heterodimer bound to DNA. Science 270 262-269, 1995. 

The retinoid X receptor forms heterodimers that recognize tandem repeats with variable spacings... 

In summary, a DNA-supported asymmetric interface located within the DNA-binding domains of these nuclear receptors provides the molecular basis for receptor heterodimers to distinguish between closely related response elements. RXR can provide a repertoire of different dimerization surfaces, each one unique for a specific partner, allowing dimers to form that are adapted to the length of the spacer region in their corresponding response elements. 

Figure 10.12 Response elements for heterodimers of the nuclear receptor for ds-retinoic acid (RXR) with the receptors for vitamin D (VDR), thyroid hormone (TR) and trans-retinoic acid (RAR). The half-sites of these response elements have identical nucleotide sequences and are organized as direct repeats. They differ in the number of base pairs in the spacer region between the half-sites. This difference forms the basis for the ability of the heterodimers to discriminate between the different response elements.

The ability of the leucine zipper proteins to form heterodimers greatly expands the repertoire of DNA-binding specificities that these proteins can display. As illustrated in Figure 10.19, for example, three distinct DNA-binding specificities could, in principle, be generated from two types of monomer, while six could be created from three types of monomer and so on. This is an example of combinatorial control, in which combinations of proteins, rather than individual proteins, control a cellular process. It is one of the most important mechanisms used by eucaryotic cells to control gene expression. 

Figure 10.19 Heterodimerization of leucine zipper proteins can alter their DNA-binding specificity. Leucine zipper homodimers bind to symmetric DNA sequences, as shown In the left-hand and center drawings. These two proteins recognize different DNA sequences, as indicated by the red and blue regions in the DNA. The two different monomers can combine to form a heterodimer that recognizes a hybrid DNA sequence, composed of one red and one blue region.

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... 

Dimerization of the Ce-zinc cluster transcription factors involves an a-helical coiled coil in the dimerization region. Coiled coils, often called leucine zippers, are also found in a large group of transcription factors that do not contain zinc. The leucine zipper is made up of two a helices in a coiled coil with every seventh residue leucine or some other large hydrophobic residue, such as isoleucine or valine. Leucine zipper transcription factors (b/zip) include factors characterized by heterodimerization, for example Fos and Jun. The a-helical DNA-binding motifs of the heterodimers recognize quite different base sequences and are continous with the a helices of the zipper. 

Helix-loop-helix (b/HLH) transcription factors are either heterodimers or homodimers with basic a-helical DNA-binding regions that lie across the major groove, rather than along it, and these helices extend into the four-helix bundle that forms the dimerization region. A modification of the b/HLH structure is seen in some transcription factors (b/HLH/zip) in which the four-helix bundle extends into a classic leucine zipper. 

Figure 13.13 (a) Schematic diagram of the Gpy heterodimer from transducln. The view Is along the central tunnel. The seven four-stranded p sheets that form the seven blades of the propeller-llke structure are labeled SI to S7. The strands are colored to highlight the seven WD sequence repeats. The N-termlnal a helices of the p and y chains form a colled coll. 

The leucine zipper DNA-binding proteins, described in Chapter 10, are examples of globular proteins that use coiled coils to form both homo- and heterodimers. A variety of fibrous proteins also have heptad repeats in their sequences and use coiled coils to form oligomers, mainly dimers and trimers. Among these are myosin, fibrinogen, actin cross-linking proteins such as spectrin and dystrophin as well as the intermediate filament proteins keratin, vimentin, desmin, and neurofilament proteins. 

Wang, J., et al. Atomic structure of an ap T-cell receptor (TCR) heterodimer in complex with an anti-TCR Fab fragment derived from a mitogenic antibody. EMBO J. 17 10-26, 1988. 

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