Structural Insights into the Polymorphism of Amyloid-Like Fibrils Formed by Region 20-29 of Amylin Revealed by Solid-State NMR and X-ray Fiber Diffraction
Structural Insights into the Polymorphism of Amyloid-Like Fibrils Formed by Region 20-29 of Amylin Revealed by Solid-State NMR and X-ray Fiber Diffraction
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DOI：
10.1021/ja802483d
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发表时间：
2008-11-12
影响因子：
15
通讯作者：
Middleton, David A.
中科院分区：
文献类型：
--
作者：
Madine, Jillian;Jack, Edward;Middleton, David A.
许多不相关的蛋白质和肽可以组装成淀粉样蛋白或淀粉样蛋白样纳米结构，所有这些都共享沿原纤维轴沿着氢键键合的β链重复阵列的交叉β基序。然而，矛盾的是，结构多态性原纤维可能来自相同的初始多肽序列。在此，肽hIAPP（20-29）的淀粉样原纤维的固态核磁共振（SSNMR）分析（对应于人胰岛淀粉样多肽胰淀素的S（20）NNFGAILSS（29）区域）揭示了该肽组装成两种淀粉样形式，（1）和（2），其在分子水平上具有不同的结构。hIAPP（20-29）原纤维的骨架F23和126之间的C-13偶极偶联的旋转共振SSNMR测量与在原丝单元的β-折叠层内具有平行β-链的形式（1）和具有反平行链的形式（2）一致。用来自30个残基的胰淀素片段（hIAPP（8-37））的结构均匀的原纤维接种hIAPP（20-29）产生具有与形成（1）类似的NMR性质的形态均匀的原纤维。种子原纤维的架构的模型，提出了基于X-射线纤维衍射数据的分析，结合广泛的SSNMR约束，包括化学位移，扭转角，和原子间距离。该模型具有交叉β脊柱，包括两个β-片层，具有由残基F23，A25和L27定义的界面，其形成疏水拉链。我们认为，原纤维形式的形成能量含有反平行和平行β-链是相似的，当这两种配置可以通过疏水接触的核心，这对氨基酸序列和淀粉样蛋白多态性之间的关系具有影响。
Many unrelated proteins and peptides can assemble into amyloid or amyloid-like nanostructures, all of which share the cross-beta motif of repeat arrays of beta-strands hydrogen-bonded along the fibril axis. Yet, paradoxically, structurally polymorphic fibrils may derive from the same initial polypeptide sequence. Here, solid-state nuclear magnetic resonance (SSNMR) analysis of amyloid-like fibrils of the peptide hIAPP(20-29), corresponding to the region S(20)NNFGAILSS(29) of the human islet amyloid polypeptide amylin, reveals that the peptide assembles into two amyloid-like forms, (1) and (2), which have distinct structures at the molecular level. Rotational resonance SSNMR measurements of C-13 dipolar couplings between backbone F23 and 126 of hIAPP(20-29) fibrils are consistent with form (1) having parallel beta-strands and form (2) having antiparallel strands within the beta-sheet layers of the protofilament units. Seeding hIAPP(20-29) with structurally homogeneous fibrils from a 30-residue amylin fragment (hIAPP(8-37)) produces morphologically homogeneous fibrils with similar NMR properties to form (1). A model for the architecture of the seeded fibrils is presented, based on the analysis of X-ray fiber diffraction data, combined with an extensive range of SSNMR constraints including chemical shifts, torsional angles, and interatomic distances. The model features a cross-beta spine comprising two beta-sheets with an interface defined by residues F23, A25, and L27, which form a hydrophobic zipper. We suggest that the energies of formation for fibril form containing antiparallel and parallel beta-strands are similar when both configurations can be stabilized by a core of hydrophobic contacts, which has implications for the relationship between amino acid sequence and amyloid polymorphism in general.