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Two Distinct Polymorphic Folding States of Self-Assembly of the Non-amyloid-β Component Differ in the Arrangement of the Residues
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2017-09-19 00:00:00 , DOI: 10.1021/acschemneuro.7b00334
Maya Pollock-Gagolashvili 1 , Yifat Miller 1
Affiliation  

Parkinson’s disease is a degenerative disorder of the central nervous system. It is characterized by presence of Lewy bodies (LBs), in which the main components of the LBs are α-synuclein (AS) aggregates. The central domain of AS, known as the “non-amyloid-β component” (NAC) is responsible for the aggregation properties of AS. It is proposed that AS fibrillar structure is a well-packed cross-β structure of the NAC domains, while the N- and C-termini are disordered. Therefore, the study of the self-assembly of NAC domains is crucial in order to understand the molecular mechanisms of AS aggregation. This is a first study that illustrates two distinct polymorphic folding states of NAC that differ in the arrangement of the residues along the sequence. One of the polymorphic folding states reveals a conformational change that is similar to the other polymorphic folding state in the backbone shape but differs in the arrangement of the residues along the backbone. This work provides insight into the molecular mechanisms through which AS can self-assembled in two different pathways yielding a conformational change between the two polymorphic folding states.

中文翻译:

残基排列中非淀粉样β组分自组装的两个不同的多态折叠状态。

帕金森氏病是中枢神经系统的变性疾病。它的特征在于路易体(LB)的存在,其中LB的主要成分是α-突触核蛋白(AS)聚集体。AS的中央域称为“非淀粉样β成分”(NAC),负责AS的聚集特性。提出AS原纤维结构是NAC结构域的堆积良好的交叉β结构,而N末端和C末端是无序的。因此,研究NAC结构域的自组装对于了解AS聚集的分子机制至关重要。这是第一项研究,它说明了NAC的两个不同的多态折叠状态,这些状态在残基沿序列的排列上有所不同。一种多态折叠状态揭示了构象变化,该构象变化与主链形状中的另一种多态折叠状态相似,但是残基沿主链的排列不同。这项工作提供了深入的分子机制,通过这些分子,AS可以在两个不同的途径中自组装,从而在两个多态折叠状态之间产生构象变化。
更新日期:2017-09-19
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