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研究揭示帕金森氏病中LRRK2的结构和微管相互作用模型
2020-08-21 19:21

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。

研究人员表示,富含亮氨酸重复的激酶2(LRRK2)是家族性帕金森氏病(PD)中最常见的突变基因,也与其特发性形式相关。LRRK2被认为在膜运输中起作用,并与微管共定位。尽管LRRK2对于理解和治疗PD至关重要,但是关于它的结构信息却很少。
 
研究人员报告了LRRK2催化部分的3.5Å结构,以及一个微管相关LRRK2的原子模型,该模型使用已报道的14Å低温电子断层扫描原位结构建立。研究人员认为,LRRK2激酶结构域的构象调节其微管相互作用,而封闭的构象则有利于微管的寡聚。研究人员发现,LRRK2的催化部分足以形成细丝,并在体外阻止微管马达驱动蛋白kinesin-1和细胞质dynein-1的运动。稳定开放构象的激酶抑制剂可缓解这种干扰并减少细胞中LRRK2细丝的形成,而稳定封闭构象的激酶抑制剂则不能。
 
这些发现表明,LRRK2可以充当微管运动的障碍,并且对治疗性LRRK2激酶抑制剂的设计具有影响。
 
附:英文原文

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:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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