Disulfide-dependent multimeric assembly of resistin family hormones
Disulfide-dependent multimeric assembly of resistin family hormones
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DOI：
10.1126/science.1093466
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发表时间：
2004-05-21
期刊：
影响因子：
56.9
通讯作者：
Shapiro, L
中科院分区：
文献类型：
--
作者：
Patel, SD;Rajala, MW;Shapiro, L
抵抗素是抵抗素样分子（RELM）激素家族的创始成员，选择性地从脂肪细胞分泌，并诱导肝脏特异性拮抗胰岛素作用，从而提供肥胖和糖尿病之间的潜在分子联系。晶体结构中的α-葡糖苷酸和β-葡糖苷酸揭示了一个不寻常的多聚体结构。每个原聚体包含羧基末端富含二硫化物的β-夹心“头部”结构域和氨基末端α-螺旋“尾部”区段。α-螺旋区段缔合以形成三链卷曲螺旋，并且表面暴露的链间二硫键介导尾对尾六聚体的形成。对血清样本的分析表明，BcN以两种不同的组装状态循环，可能对应于六聚体和三聚体。在胰腺-胰岛素钳夹研究中，输注缺乏三聚体间二硫键的突变体，对肝脏胰岛素敏感性的影响比野生型突变体对肝脏胰岛素敏感性的影响更大。该结果表明，三聚体间二硫键的加工可能反映了朝向活化的强制性步骤。
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 wildtype resistin. This result suggests that processing of the intertrimer disulfide bonds may reflect an obligatory step toward activation.