Growth hormone receptor binding domains

The prolactin receptor, PER, which regulates milk production in mammals, belongs to the same receptor class as the growth hormone receptor. In addition to binding the hormone prolactin, PER also binds and is activated by growth hormone. The extracellular domain of PER forms a very stable 1 1 complex with growth hormone in solution this complex has been crystallized and its structure determined (Figure 13.21). We shall compare this structure with the 1 2 complex of the same hormone with GHR. 

Figure 13.23 The F-G loop in the C-terminal domain of the prolactin receptor is involved in a unique interaction, (a) The F-G loop of the growth hormone receptor (blue) is not involved in any specific interactions with the growth hormone (red), (b) The F-G loop in the prolactin receptor forms a strong zinc-binding site that links the receptor (green) to the hormone (red). (Adapted from W. Somers et at.. Nature 372 478-481, 1994.)...

Fuh, G., Mulkerrin, M. G., Bass, S., McFarland, N., Brochier, M., Bourell, J. H., Light, D. R., and Wells, J. A. (1990). The human growth hormone receptor. Secretion from Escherichia coli and disulfide bonding pattern of the extracellular binding domain./ Biol. Ghent. 265(6), 3111-3115. 

Some ligands induce dimerization of the receptors to which they bind. Such a receptor contains an extracellular domain that binds the ligand, a transmembrane region, and a cytosolic domain that either binds or contains a protein kinase. The growth-hormone receptor participates in an example of this type of signal-transduction pathway. Dimerization of the receptor activates Janus kinase 2, a protein kinase associated with the intracellular part of the receptor. The kinase, in turn, phosphorylates and activates a transcription factor called STAT5. 

For some cytokine receptors, including the growth hormone receptor and several interleukin receptors, soluble isoforms have been described that comprise all or part of the extracellular domain and may be able to bind the extracellular ligands. By association with other subunits of heterooligomeric receptors, e. g., the gpl30 subunit, these soluble isoforms can function as agonists or antagonists. 

A given molecule of growth hormone contains two domains, each of which binds a receptor monomer. Thus, a single molecule of growth hormone could be bound by two receptors, bringing them together to form the activated hormone-receptor dimer complex. 

Figure 13.20 Ribbon diagram of the structure of a 1 2 complex between the human growth hormone and the extracellular domains of two receptor molecules. The two receptor molecules (blue) bind the hormone (red) with essentially the same loop regions (yellow).

Figure 11-13 (A) A simplified version of the mitogen-activated kinase (MAPK) signaling cascade. At left is shown a hormone receptor, e.g., that for the epidermal growth factor (EGF). The receptor tyrosine kinase undergoes autophosphorylation on numerous tyrosines. The resulting phosphotyrosyl (Y-P) groups bind to SH2 domains of adapters such as Grb2 and She.

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