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Structure and regulation of full-length human leucine-rich repeat kinase 1

Authors :
Riley D. Metcalfe
Juliana A. Martinez Fiesco
Luis Bonet-Ponce
Jillian H. Kluss
Mark R. Cookson
Ping Zhang
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-17 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

Abstract 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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723 and 34282440
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.7f9154c34282440f9b99657c8f3c4db7
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-40532-2