Othmer-Jacobs Department of Chemical and Biological Engineering, Polytechnic Institute of New York University, 6 MetroTech Center, Brooklyn, NY 11201, USA.
Chembiochem. 2011 Nov 25;12(17):2630-9. doi: 10.1002/cbic.201100430. Epub 2011 Oct 13.
The aggregation of α-synuclein (αS), which is implicated in the pathology of Parkinson's disease, produces fibrils in which layers of parallel, in-register β-sheet-loop-β-sheets are formed. The effects of sequence variation in the loop-forming region (referred to as the linker region) on αS aggregation have yet to be systematically studied. In the study described here, we created and characterized αS variants containing mutations in the linker regions. Our results indicate that although the physicochemical properties of the linker region, evaluated based on an intrinsic property of a single amino acid, still play a significant role in aggregation, additional factors can also determine aggregation of αS linker mutants. Our analyses suggest that these factors include a pairwise potential for parallel in-register β-sheet formation. A linker variant displaying significantly reduced self-aggregation interfered with αS aggregation by inhibiting the conversion of αS soluble species to αS insoluble fibrils. We anticipate that linker mutations could serve as a novel method of creating αS variants that are aggregation-defective and/or inhibit αS aggregation.
α-突触核蛋白（αS）的聚集与帕金森病的病理学有关，它会产生纤维，其中形成了平行、有序的β-折叠环-β-折叠层。然而，环形成区域（称为连接子区域）中的序列变异对αS 聚集的影响尚未得到系统研究。在本文所述的研究中，我们创建并表征了含有连接子区域突变的αS 变体。我们的结果表明，尽管连接子区域的理化性质（基于单个氨基酸的固有性质进行评估）在聚集中仍然起着重要作用，但其他因素也可以决定 αS 连接子突变体的聚集。我们的分析表明，这些因素包括平行有序β-折叠形成的成对潜力。显示出显著降低自聚集能力的连接子变体通过抑制αS 可溶性物种向αS 不溶性纤维的转化来干扰αS 聚集。我们预计连接子突变可以作为一种新的方法来创建聚集缺陷和/或抑制αS 聚集的αS 变体。
