Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules

IF 16.8 1区 生物学
D. Snead, M. Matyszewski, Andrea M. Dickey, Yu Lin, A. Leschziner, Samara L. Reck-Peterson
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引用次数: 11

Abstract

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson’s Disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-electron microscopy structure of the catalytic half of LRRK2, containing its kinase, which is in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2, but is not linked to PD. LRRK1’s structure is similar to LRRK2, but LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2’s GTPase domain that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2’s kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.
帕金森病相关LRRK2与微管结合的结构基础
亮氨酸富重复激酶2 (LRRK2)是家族性帕金森病(PD)中最常见的突变基因之一。在某些情况下,LRRK2与细胞中的微管共定位,PD突变增强了这种关联。我们报道了LRRK2的催化一半的低温电镜结构,包含其激酶,这是一个封闭的构象,和GTPase结构域,结合到微管。我们还报道了LRRK1催化一半的结构,它与LRRK2密切相关,但与PD无关。LRRK1的结构与LRRK2相似,但LRRK1不与微管相互作用。在这些结构的指导下,我们在LRRK2的GTPase结构域中鉴定了介导微管结合的氨基酸;突变它们会破坏体外和细胞内的微管结合,而不会影响LRRK2的激酶活性。我们的研究结果对治疗性LRRK2激酶抑制剂的设计具有启示意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nature Structural &Molecular Biology
Nature Structural &Molecular Biology 生物-生化与分子生物学
自引率
1.80%
发文量
160
期刊介绍: Nature Structural & Molecular Biology is a monthly journal that focuses on the functional and mechanistic understanding of how molecular components in a biological process work together. It serves as an integrated forum for structural and molecular studies. The journal places a strong emphasis on the functional and mechanistic understanding of how molecular components in a biological process work together. Some specific areas of interest include the structure and function of proteins, nucleic acids, and other macromolecules, DNA replication, repair and recombination, transcription, regulation of transcription and translation, protein folding, processing and degradation, signal transduction, and intracellular signaling.
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