Atomic structures of IAPP (amylin) fusions suggest a mechanism for fibrillation and the role of insulin in the process
Atomic structures of IAPP (amylin) fusions suggest a mechanism for fibrillation and the role of insulin in the process
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DOI：
10.1002/pro.145
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发表时间：
2009-07-01
期刊：
影响因子：
8
通讯作者：
Eisenberg, David
中科院分区：
文献类型：
--
作者：
Wiltzius, Jed J. W.;Sievers, Stuart A.;Eisenberg, David
胰岛淀粉样多肽（IAPP或amylin）是一种与胰岛素一起在胰岛细胞中产生和储存的肽激素。IAPP在体外容易形成淀粉样原纤维，纤维状IAPP的沉积与II型糖尿病的病理有关。IAPP从可溶性到纤维状的转化机制尚不清楚。通过跟踪IAPP与麦芽糖结合蛋白的融合，我们发现IAPP在8-18和22-27残基处呈a-螺旋结构，并且IAPP分子二聚化。突变分析表明，这种二聚化是纤颤的途径之一。该结构表明IAPP可能与胰岛素异二聚，我们通过蛋白交联证实了这一点。综上所述，这些实验表明IAPP的螺旋二聚化加速了纤维的形成，而胰岛素通过阻断IAPP二聚化界面来阻止纤维的形成。
Islet Amyloid Polypeptide (IAPP or amylin) is a peptide hormone produced and stored in the beta-islet cells of the pancreas along with insulin. IAPP readily forms amyloid fibrils in vitro, and the deposition of fibrillar IAPP has been correlated with the pathology of type II diabetes. The mechanism of the conversion that IAPP undergoes from soluble to fibrillar forms has been unclear. By chaperoning IAPP through fusion to maltose binding protein, we find that IAPP can adopt a a-helical structure at residues 8-18 and 22-27 and that molecules of IAPP dimerize. Mutational analysis suggests that this dimerization is on the pathway to fibrillation. The structure suggests how IAPP may heterodimerize with insulin, which we confirmed by protein crosslinking. Taken together, these experiments suggest the helical dimerization of IAPP accelerates fibril formation and that insulin impedes fibrillation by blocking the IAPP dimerization interface.