Structure and regulation of full-length human leucine-rich repeat kinase 1.
Structure and regulation of full-length human leucine-rich repeat kinase 1.
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DOI：
10.1038/s41467-023-40532-2
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发表时间：
2023-08-09
影响因子：
16.6
通讯作者：
Zhang, Ping
中科院分区：
文献类型：
--
作者：
Metcalfe, Riley D.;Martinez Fiesco, Juliana A.;Bonet-Ponce, Luis;Kluss, Jillian H.;Cookson, Mark R.;Zhang, Ping
人类富含亮氨酸重复序列激酶（LRRKs），LRRK 1和LRRK 2是大的且异常复杂的多结构域激酶，其调节基本细胞过程并与人类疾病有关。LRRK 2的结构最近已经确定，但调节LRRK 1活性的结构和分子机制以及LRRK 1和LRRK 2调节的差异仍不清楚。在这里，我们报告的LRRK 1单体的冷冻-EM结构和LRRK 1二聚体的低分辨率冷冻-EM图。单体结构，其中激酶是在一个非活性构象，揭示了关键的域间接口，控制激酶活性，我们验证实验。与LRRK 2相比，LRRK 1单体和二聚体在结构上是不同的。总的来说，我们的研究结果提供了对人类LRRKs激活的结构性见解，这促进了我们对其生理和病理作用的理解。富含亮氨酸的重复序列激酶1（LRRK 1）及其对应物LRRK 2在调节基本细胞过程中起着至关重要的作用。在这里，作者使用cryo-EM来表征LRRK 1单体和二聚体，揭示了调节激酶活性的界面和与LRRK 2的结构差异。
The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human disease. Structures of LRRK2 have recently been determined, but the structure and molecular mechanisms regulating the activity of the LRRK1 as well as differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces that control kinase activity as we validate experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2. Overall, our results provide structural insights into the activation of the human LRRKs, which advance our understanding of their physiological and pathological roles. Leucine-rich repeat kinase 1 (LRRK1) and its counterpart LRRK2 play crucial roles in regulating fundamental cellular processes. Here, the authors use cryo-EM to characterize the LRRK1 monomer and dimer, revealing interfaces that regulate kinase activity and structural differences to LRRK2.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
12.7
作者：
Fan Y;Nirujogi RS;Garrido A;Ruiz-Martínez J;Bergareche-Yarza A;Mondragón-Rezola E;Vinagre-Aragón A;Croitoru I;Gorostidi Pagola A;Paternain Markinez L;Alcalay R;Hickman RA;Düring J;Gomes S;Pratuseviciute N;Padmanabhan S;Valldeoriola F;Pérez Sisqués L;Malagelada C;Ximelis T;Molina Porcel L;Martí MJ;Tolosa E;Alessi DR;Sammler EM
通讯作者：
Sammler EM
影响因子：
4.8
作者：
Greggio, Elisa;Zambrano, Ibardo;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
4.8
作者：
Korr, D;Toschi, L;Weiss, B
通讯作者：
Weiss, B
影响因子：
2.9
作者：
Ito, Genta;Okai, Takuro;Iwatsubo, Takeshi
通讯作者：
Iwatsubo, Takeshi