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Science 21 May 2004:
Vol. 304. no. 5674, pp. 1154 - 1158
DOI: 10.1126/science.1093466
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Reports

Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones

Saurabh D. Patel,1 Michael W. Rajala,2 Luciano Rossetti,3,4 Philipp E. Scherer,2,3,4 Lawrence Shapiro1,5,6*

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 RELMß reveal an unusual multimeric structure. Each protomer comprises a carboxy-terminal disulfide-rich ß-sandwich "head" domain and an amino-terminal {alpha}-helical "tail" segment. The {alpha}-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.

1 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
2 Department of Cell Biology, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3 Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4 Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
5 Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.
6 Edward S. Harkness Eye Institute, Columbia University, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: lss8{at}columbia.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)