Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases.
Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases.
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DOI：
10.1371/journal.pcbi.1000476
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发表时间：
2009-08
影响因子：
4.3
通讯作者：
Ventura S
中科院分区：
文献类型：
--
作者：
Castillo V;Ventura S
蛋白质聚集是人类一系列疾病的基础。这些病理过程中涉及的多肽可能本质上是非结构化的，或者显示出定义的3D结构。关于球状蛋白在生理条件下如何聚集成有毒组件，在那里它们显示出最初折叠的构象，人们知之甚少。然而，蛋白质聚集总是由异常蛋白质-蛋白质相互作用的建立启动的。因此，在目前的工作中，我们探索了与构象疾病相关的球状蛋白中蛋白质相互作用表面和聚集倾向区域重叠的程度。对这些蛋白质形成的天然复合体的计算分析表明，容易聚集的区域确实经常与蛋白质界面重叠。相互作用部位和聚集区的空间重合表明，功能复合体的形成及其单个亚基的聚集可能在细胞内竞争。因此，影响复杂界面或稳定性的单个突变通常会导致有毒聚集体的形成。因此，稳定多聚体蛋白的现有界面或在单体多肽中形成新的复合体可能成为防止球状蛋白疾病相关聚集的有效策略。蛋白质在组织中的聚集与40多种人类疾病的发病机制有关。阿尔茨海默氏症和帕金森氏症等疾病的潜在多肽缺乏任何规则的结构，而导致家族性肌萎缩侧索硬化症或非神经病理性系统性淀粉样变性的多肽对应于球状蛋白。关于球状蛋白在生理条件下从最初折叠的和可溶的构象聚集的机制，人们知之甚少。有趣的是，这些致病蛋白中的一些呈现四级结构或在其生理环境中与其他蛋白结合。在目前的工作中，我们发现这些多肽中的蛋白质-蛋白质相互作用面和高聚集倾向的区域显著重叠。这表明，天然复合体的形成和自我聚集反应可能在细胞内竞争，这解释了为什么影响界面或蛋白质复合体稳定性的点突变在许多情况下会导致有毒聚集体的形成。这项研究提出了对抗与球状多肽沉积相关的疾病的一般策略。
Protein aggregation underlies a wide range of human disorders. The polypeptides involved in these pathologies might be intrinsically unstructured or display a defined 3D-structure. Little is known about how globular proteins aggregate into toxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however, always initiated by the establishment of anomalous protein-protein interactions. Therefore, in the present work, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteins associated with conformational diseases. Computational analysis of the native complexes formed by these proteins shows that aggregation-prone regions do frequently overlap with protein interfaces. The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell. Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates. It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins. The aggregation of proteins in tissues is associated with the pathogenesis of more than 40 human diseases. The polypeptides underlying disorders such as Alzheimer's and Parkinson's are devoid of any regular structure, whereas the polypeptides causing familial amyotrophic lateral sclerosis or nonneuropathic systemic amyloidosis correspond to globular proteins. Little is known about the mechanism by which globular proteins under physiological conditions aggregate from their initially folded and soluble conformations. Interestingly, several of these pathogenic proteins display quaternary structure or are bound to other proteins in their physiological context. In the present work, we show that protein-protein interaction surfaces and regions with high aggregation propensity significantly overlap in these polypeptides. This suggests that the formation of native complexes and self-aggregation reactions probably compete in the cell, explaining why point mutations affecting the interface or the stability of the protein complex lead in many cases to the formation of toxic aggregates. This study proposes general strategies to fight against diseases associated with the deposition of globular polypeptides.
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DOI：
10.1073/pnas.0303758100
发表时间：
2003-12-23
影响因子：
11.1
作者：
Fändrich, M;Forge, V;Diekmann, S
通讯作者：
Diekmann, S
影响因子：
6.8
作者：
Bellotti, Vittorio;Chiti, Fabrizio
通讯作者：
Chiti, Fabrizio
DOI：
10.1038/nsb935
发表时间：
2003-06-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Elam, JS;Taylor, AB;Hart, PJ
通讯作者：
Hart, PJ
影响因子：
3
作者：
Conchillo-Solé O;de Groot NS;Avilés FX;Vendrell J;Daura X;Ventura S
通讯作者：
Ventura S
影响因子：
11.4
作者：
Chiti, F;Taddei, N;Dobson, CM
通讯作者：
Dobson, CM