Three-dimensional structure and orientation of rat islet amyloid polypeptide protein in a membrane environment by solution NMR spectroscopy.
Three-dimensional structure and orientation of rat islet amyloid polypeptide protein in a membrane environment by solution NMR spectroscopy.
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DOI：
10.1021/ja9010095
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发表时间：
2009-06-17
影响因子：
15
通讯作者：
Ramamoorthy A
中科院分区：
文献类型：
--
作者：
Nanga RP;Brender JR;Xu J;Hartman K;Subramanian V;Ramamoorthy A
胰岛淀粉样多肽（IAPP 或胰淀素）是一种与葡萄糖代谢相关的 37 个残基肽激素，由胰腺中的 β 细胞与胰岛素共同分泌。由于人 IAPP 是一种高度淀粉样蛋白生成肽，因此有人认为 IAPP 淀粉样蛋白纤维的形成是 II 型糖尿病早期阶段 β 细胞死亡的原因。据推测，人类 IAPP 的瞬时膜结合 α 螺旋结构是这些淀粉样蛋白沉积物形成的前体。另一方面，大鼠 IAPP 形成短暂的 α 螺旋结构，但不会进一步形成淀粉样原纤维。为了了解这种中间状态的性质以及大鼠和人类版本 IAPP 之间的毒性差异，我们解析了由十二烷基磷酸胆碱组成的模拟膜洗涤剂胶束中大鼠 IAPP 的高分辨率结构。该结构的特征是横跨残基 A5 至 S23 的螺旋区域和无序的 C 末端。在 R18 和 S19 处观察到螺旋变形，这可能与受体结合有关。顺磁淬灭 NMR 实验表明，大鼠 IAPP 结合在胶束表面，这与 IAPP 的其他无毒形式一致。与其他 IAPP 变体的去污剂结合结构的比较表明，N 端区域可能通过控制两亲螺旋疏水面上假定的二聚化界面的进入，在 IAPP 的自缔合和毒性中发挥关键作用。
Islet amyloid polypeptide (IAPP or amylin) is a 37-residue peptide hormone associated with glucose metabolism that is cosecreted with insulin by β-cells in the pancreas. Since human IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers is responsible for the death of β-cells during the early stages of type II diabetes. It has been hypothesized that transient membrane-bound α-helical structures of human IAPP are precursors to the formation of these amyloid deposits. On the other hand, rat IAPP forms transient α-helical structures but does not progress further to form amyloid fibrils. To understand the nature of this intermediate state and the difference in toxicity between the rat and human versions of IAPP, we have solved the high-resolution structure of rat IAPP in the membrane-mimicking detergent micelles composed of dodecylphosphocholine. The structure is characterized by a helical region spanning the residues A5 to S23 and a disordered C-terminus. A distortion in the helix is seen at R18 and S19 that may be involved in receptor binding. Paramagnetic quenching NMR experiments indicate that rat IAPP is bound on the surface of the micelle, in agreement with other nontoxic forms of IAPP. A comparison to the detergent-bound structures of other IAPP variants indicates that the N-terminal region may play a crucial role in the self-association and toxicity of IAPP by controlling access to the putative dimerization interface on the hydrophobic face of the amphipathic helix.
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