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首页> 外文期刊>Journal of Molecular Biology >Structure of a Single-Chain Fv Bound to the 17 N-Terminal Residues of Huntingtin Provides Insights into Pathogenic Amyloid Formation and Suppression
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Structure of a Single-Chain Fv Bound to the 17 N-Terminal Residues of Huntingtin Provides Insights into Pathogenic Amyloid Formation and Suppression

机译：单链Fv绑定到Huntingtin的17 N末端残基的结构提供了对致病性淀粉样蛋白形成和抑制的见解。

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摘要

Huntington's disease is triggered by misfolding of fragments of mutant forms of the huntingtin protein (mHTT) with aberrant polyglutamine expansions. The C4 single-chain Fv antibody (scFv) binds to the first 17 residues of huntingtin [HTT(1-17)] and generates substantial protection against multiple phenotypic pathologies in situ and in vivo. We show in this paper that C4 scFv inhibits amyloid formation by exon1 fragments of huntingtin in vitro and elucidate the structural basis for this inhibition and protection by determining the crystal structure of the complex of C4 scFv and HTT(1-17). The peptide binds with residues 3-11 forming an amphipathic helix that makes contact with the antibody fragment in such a way that the hydrophobic face of this helix is shielded from the solvent. Residues 12-17 of the peptide are in an extended conformation and interact with the same region of another C4 scFv:HTT(1-17) complex in the asymmetric unit, resulting in a beta-sheet interface within a dimeric C4 scFv:HTT(1-17) complex. The nature of this scFv peptide complex was further explored in solution by high-resolution NMR and physicochemical analysis of species in solution. The results provide insights into the manner in which C4 scFv inhibits the aggregation of HTT, and hence into its therapeutic potential, and suggests a structural basis for the initial interactions that underlie the formation of disease-associated amyloid fibrils by HIT. (C) 2015 The Authors. Published by Elsevier Ltd.
机译：亨廷顿氏病是由于亨廷顿蛋白（mHTT）突变形式的片段与错误的聚谷氨酰胺膨胀错误折叠引起的。 C4单链Fv抗体（scFv）与亨廷顿蛋白[HTT（1-17）]的前17个残基结合，并针对原位和体内的多种表型病理产生实质性保护。我们在本文中显示C4 scFv在体外抑制亨廷顿蛋白外显子1片段形成的淀粉样蛋白，并通过确定C4 scFv和HTT（1-17）的复合物的晶体结构阐明了这种抑制和保护的结构基础。该肽与残基3-11结合，形成两亲性螺旋，该螺旋与抗体片段接触，从而使该螺旋的疏水面与溶剂隔离。肽的残基12-17处于延长的构象，并与不对称单元中另一个C4 scFv：HTT（1-17）复合物的相同区域相互作用，从而在二聚C4 scFv：HTT（ 1-17）复杂。通过高分辨率NMR和溶液中物质的物理化学分析，进一步研究了该scFv肽复合物的性质。结果为C4 scFv抑制HTT聚集的方式提供了见识，因此也为它的治疗潜力提供了见识，并为HIT形成疾病相关淀粉样蛋白原纤维的初始相互作用提供了结构基础。 （C）2015作者。由Elsevier Ltd.发布

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