PubMed · 7984232
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F Jurnak. 1994-12-01. Protein-protein interaction. Complex flexibility.. https://doi.org/10.1038/372409a0
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Binding reactions between human growth hormone (hGH) and its receptor provide a detailed account of how a polypeptide hormone activates its receptor and more generally how proteins interact. Through high-resolution structural and functional studies it is seen that hGH uses two different sites (site 1 and site 2) to bind two identical receptor molecules. This sequential dimerization reaction activates the receptor, presumably by bringing the intracellular domains into close proximity so they may activate cytosolic components. As a consequence of this mechanism it is possible to build antagonists to the receptor by introducing mutations in hGH that block binding at site 2 and to build even more potent antagonists by combining these with mutants that enhance binding at site 1. Alanine-scanning mutagenesis of all contact residues at the site 1 interface shows that only a small and complementary set of side chains clustered near the center of the interface affects binding. The most important contacts are hydrophobic, and these are surrounded by polar and charged interactions of lesser importance. Kinetic analysis shows for the most part that the important side chains function to maintain the complex, not to guide the hormone to the receptor. Hormone-induced homodimerization or heterodimerization reactions are turning out to be pervasive mechanisms for signal transduction. Moreover, the molecular recognition principles seen in the hGH-receptor complex are likely to generalize to other protein-protein complexes.
Many of the metabolic actions of growth hormone (GH) are mediated through insulin-like growth factors or somatomedins. Recombinant human insulin-like growth factor-I (rhIGF-I) has a dichotomous insulin-like and GH-like action when used in different clinical situations in humans. Its effects on carbohydrate metabolism show a prominent increase in total insulin sensitivity, causing hypoglycemia in higher doses and maintaining normal glucose homeostasis in lower doses. This polypeptide selectively stimulates whole body protein synthesis with no effect on proteolysis when given in doses of 100 micrograms/ kg subcutaneously twice daily for at least 5-7 days, effects which are indistinguishable from those of GH. This contrasts with the marked suppression of proteolysis observed when higher doses are given, similar to the effects observed with insulin. When used in combination with rhGH, rhIGF-I has a synergistic effect, improving total nitrogen retention in calorically deprived subjects, yet it does not cause any greater enhancement of whole body protein anabolism in normally fed volunteers than giving rhGH and rhIGF-I individually. This suggests a common pathway for IGF-I and GH enhancing protein anabolism in the normally fed state. rhIGF-I also stimulates linear growth in children with defects in the GH receptor. Recent data show that this potent growth factor has a potential advantage over GH in the treatment of severe protein catabolic states, particularly the glucocorticosteroid-dependent model, as it ameliorates the marked increase in protein catabolism caused by the steroids, but without a diabetogenic effect. Here, a brief overview is provided of available human data on the actions of this peptide on carbohydrate, lipid, and protein metabolism, linear growth, and its anabolic effects. rhIGF-I offers promise in the treatment of selective growth disorders and in protein catabolic and insulin-resistant states.
Reciprocal communication between the neuroendocrine and immune systems is critical to the establishment of host homeostatic and defence mechanisms. The production and utilisation of common ligands and their receptors by cells of the immune and neuroendocrine systems constitutes a biochemical information circuit between and within the immune and neuroendocrine systems. Although the structures of the various signalling components appear to be similar in both systems, the regulation of their synthesis may be different. Growth hormone and prolactin have similar and marked influences on the function/activity of each of the major immune cell types, both in vitro and in vivo. The underlying molecular mechanisms are just beginning to be unravelled, and it is anticipated that further work in this rapidly developing field will establish abnormal pituitary and/or lymphocyte growth hormone and prolactin synthesis and function as a contributory factor to a number of pathologic situations, including leukaemia and autoimmunity.