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Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones

Science  21 May 2004:
Vol. 304, Issue 5674, pp. 1154-1158
DOI: 10.1126/science.1093466

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Abstract

Resistin, founding member of the resistin-like molecule (RELM) hormone family, is secreted selectively from adipocytes and induces liver-specific antagonism of insulin action, thus providing a potential molecular link between obesity and diabetes. Crystal structures of resistin and RELMβ reveal an unusual multimeric structure. Each protomer comprises a carboxy-terminal disulfide-rich β-sandwich “head” domain and an amino-terminal α-helical “tail” segment. The α-helical segments associate to form three-stranded coiled coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. Analysis of serum samples shows that resistin circulates in two distinct assembly states, likely corresponding to hexamers and trimers. Infusion of a resistin mutant, lacking the intertrimer disulfide bonds, in pancreatic-insulin clamp studies reveals substantially more potent effects on hepatic insulin sensitivity than those observed with wild-type resistin. This result suggests that processing of the intertrimer disulfide bonds may reflect an obligatory step toward activation.

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