美国加州大学圣地亚哥分校A. E. Leschziner、S. L. Reck-Peterson等研究人员合作揭示帕金森氏病中LRRK2的结构和微管相互作用模型。2020年8月19日,《自然》杂志在线发表了这项成果。
Title: Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction
Author: C. K. Deniston, J. Salogiannis, S. Mathea, D. M. Snead, I. Lahiri, M. Matyszewski, O. Donosa, R. Watanabe, J. Bhning, A. K. Shiau, S. Knapp, E. Villa, S. L. Reck-Peterson, A. E. Leschziner
Issue&Volume: 2020-08-19
Abstract: Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson’s disease (PD)1 and is also linked to its idiopathic form2. LRRK2 is proposed to function in membrane trafficking3 and co-localizes with microtubules4. Despite LRRK2’s fundamental importance for understanding and treating PD, there is limited structural information on it. Here we report the 3.5Å structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14Å cryo-electron tomography in situ structure5. We propose that the conformation of LRRK2’s kinase domain regulates its microtubule interaction, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin-1 and cytoplasmic dynein-1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce LRRK2 filament formation in cells, while those that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.
DOI: 10.1038/s41586-020-2673-2
Source: https://www.nature.com/articles/s41586-020-2673-2
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html