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帕金森病相关蛋白LRRK2的结构获解析
作者:小柯机器人 发布时间:2020/8/13 15:40:21

帕金森病相关蛋白富亮氨酸重复激酶2(LRRK2)的原位结构获解析,这一成果由美国加州大学圣地亚哥分校Elizabeth Villa研究组经过不懈努力而取得。2020年8月11日出版的《细胞》在线发表了这项成果。

使用光镜-电镜关联成像、原位冷冻电子断层扫描和断层图分析,研究人员揭示了带有致病性突变LRRK2的14 Å结构,其围绕微管寡聚为右手双螺旋,而其本身为左手螺旋。使用整合建模,研究人员确定了LRRK2的体系结构,表明GTPase和激酶非常接近,GTPase靠近微管表面,而激酶则暴露于细胞质。

研究人员发现了由非催化域构成的两个低聚界面。突变其中任何一个则消除LRRK2与微管的关联。该工作证明了低温电子断层扫描在细胞水平的结构模型能力,其可以揭示先前未知的细胞结构。

研究人员表示,LRRK2突变是家族性帕金森病的最常见原因。LRRK2是包含激酶和GTPase的多结构域蛋白。

附:英文原文

Title: The In Situ Structure of Parkinson’s Disease-Linked LRRK2

Author: Reika Watanabe, Robert Buschauer, Jan Bhning, Martina Audagnotto, Keren Lasker, Tsan-Wen Lu, Daniela Boassa, Susan Taylor, Elizabeth Villa

Issue&Volume: 2020-08-11

Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familialParkinson’s disease. LRRK2 is a multi-domain protein containing a kinase and GTPase.Using correlative light and electron microscopy, in situ cryo-electron tomography, and subtomogram analysis, we reveal a 14- structure ofLRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double helixaround microtubules, which are left-handed. Using integrative modeling, we determinethe architecture of LRRK2, showing that the GTPase and kinase are in close proximity,with the GTPase closer to the microtubule surface, whereas the kinase is exposed tothe cytoplasm. We identify two oligomerization interfaces mediated by non-catalyticdomains. Mutation of one of these abolishes LRRK2 microtubule-association. Our workdemonstrates the power of cryo-electron tomography to generate models of previouslyunsolved structures in their cellular environment.

DOI: 10.1016/j.cell.2020.08.004

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30995-8

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/