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Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization

机译：稳定的二聚体的晶体结构揭示了丝氨酸蛋白酶抑制剂聚合的分子基础

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摘要

Repeating intermolecular protein association by means of β-sheet expansion is the mechanism underlying a multitude of diseases including Alzheimer's, Huntington's and Parkinson's and the prion encephalopathies. A family of proteins, known as the ser-pins, also forms large stable multimers by ordered P-sheet linkages leading to intracellular accretion and disease. These 'serpin-opathies' include early-onset dementia caused by mutations in neu-roserpin, liver cirrhosis and emphysema caused by mutations in α_1-antitrypsin (α_1AT), and thrombosis caused by mutations in antithrombin. Serpin structure and function are quite well understood, and the family has therefore become a model system for understanding the P-sheet expansion disorders collectively known as the conformational diseases. To develop strategies to prevent and reverse these disorders, it is necessary to determine the structural basis of the intermolecular linkage and of the pathogenic monomeric state. Here we report the crystallographic structure of a stable serpin dimer which reveals a domain swap of more than 50 residues, including two long antiparallel β-strands inserting in the centre of the principal p-sheet of the neighbouring monomer. This structure explains the extreme stability of serpin polymers, the molecular basis of their rapid propagation, and provides critical new insights into the structural changes which initiate irreversible β-sheet expansion.
机译：通过β-折叠扩展来重复分子间蛋白质结合是包括阿尔茨海默氏病，亨廷顿氏病和帕金森氏病和the病毒脑病在内的多种疾病的潜在机制。一类称为ser-pins的蛋白质也通过有序的P-sheet连接形成大型稳定的多聚体，从而导致细胞内积聚和疾病。这些“ serpin-opathies”包括由neu-roserpin突变引起的早发性痴呆，由α_1-抗胰蛋白酶（α_1AT）突变引起的肝硬化和肺气肿，以及由抗凝血酶突变引起的血栓形成。丝氨酸蛋白酶抑制剂的结构和功能已被很好地理解，因此该家族已成为用于理解统称为构象性疾病的P-折叠扩展障碍的模型系统。为了开发预防和逆转这些疾病的策略，有必要确定分子间连接和致病性单体状态的结构基础。在这里，我们报告了稳定的丝氨酸蛋白酶抑制剂二聚体的晶体结构，揭示了超过50个残基的结构域交换，包括两个长的反平行β链插入相邻单体的主要p-sheet的中心。这种结构解释了丝氨酸蛋白酶抑制剂聚合物的极端稳定性，其快速繁殖的分子基础，并为引发不可逆的β-折叠扩展的结构变化提供了重要的新见解。

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  • 来源
    《Nature》 |2008年第7217期|p.1255-1258|共4页
  • 作者

    Masayuki Yamasaki; Wei Li; Daniel J. D. Johnson; James A. Huntington;

  • 作者单位

    University of Cambridge, Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 OXY, UK;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自然科学总论;
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