Disulfide-dependent multimeric assembly of resistin family hormones.
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 RELMbeta reveal an unusual multimeric structure. Each protomer comprises a carboxy-terminal disulfide-rich beta-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.
Patel
Saurabh D
SD
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
Rajala
Michael W
MW
Rossetti
Luciano
L
Scherer
Philipp E
PE
Shapiro
Lawrence
L
D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003460:Crystallization; D018360:Crystallography, X-Ray; D017077:Culture Media, Conditioned; D004220:Disulfides / Q000737:chemistry*; D005947:Glucose / Q000378:metabolism; D006729:Hormones, Ectopic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000097:blood; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D052243:Resistin
D052242:Adiponectin; D017077:Culture Media, Conditioned; D004220:Disulfides; D006729:Hormones, Ectopic; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C499624:RETN protein, human; D052243:Resistin; C499623:Retn protein, mouse; C486522:Retnlb protein, mouse; D005947:Glucose