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全长LRRK2的结构获解析
作者:小柯机器人 发布时间:2021/6/9 15:42:21

美国圣犹大儿童研究医院Ji Sun团队解析出全长LRRK2的结构。2021年6月8日,《细胞》杂志在线发表了这项成果。

研究人员表示,富含亮氨酸重复激酶2(LRRK2)的突变通常与家族性和散发性帕金森病(PD)的发病机制有关。LRRK2调节膜细胞器的关键细胞过程并形成基于微管的致病丝,但LRRK2这些生物学作用背后的分子基础仍然很大程度上是个谜。

研究人员解析了全长人类LRRK2的高分辨率结构,并揭示了其结构和关键的域间支架元素,可用于理解致病突变。LRRK2的激酶结构域以非活性状态被捕获,最常见的PD相关突变LRRK2G2019S也采用这种构象。这种构象可作为构象特异性抑制剂的设计框架。研究人员进一步确定了COR介导的 LRRK2二聚体的结构,并发现二聚体界面的单点突变消除了细胞中的致病丝。

总体而言,这项研究提供了对LRRK2生理和病理作用的机制见解,并为未来的PD治疗干预建立了结构模板。

附:英文原文

Title: Structural analysis of the full-length human LRRK2

Author: Alexander Myasnikov, Hanwen Zhu, Patricia Hixson, Boer Xie, Kaiwen Yu, Aaron Pitre, Junmin Peng, Ji Sun

Issue&Volume: 2021-06-08

Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesisof both familial and sporadic Parkinson’s disease (PD). LRRK2 regulates critical cellularprocesses at membranous organelles and forms microtubule-based pathogenic filaments,yet the molecular basis underlying these biological roles of LRRK2 remains largelyenigmatic. Here, we determined high-resolution structures of full-length human LRRK2,revealing its architecture and key interdomain scaffolding elements for rationalizingdisease-causing mutations. The kinase domain of LRRK2 is captured in an inactive state,a conformation also adopted by the most common PD-associated mutation, LRRK2G2019S. This conformation serves as a framework for structure-guided design of conformationalspecific inhibitors. We further determined the structure of COR-mediated LRRK2 dimersand found that single-point mutations at the dimer interface abolished pathogenicfilamentation in cells. Overall, our study provides mechanistic insights into physiologicaland pathological roles of LRRK2 and establishes a structural template for future therapeuticintervention in PD.

DOI: 10.1016/j.cell.2021.05.004

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00601-2

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/