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Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.
- Source :
-
Science . 12/22/2023, Vol. 382 Issue 6677, p1404-1411. 8p. 1 Color Photograph, 5 Graphs. - Publication Year :
- 2023
-
Abstract
- Gain-of-function mutations in LRRK2, which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the PARK16 locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00368075
- Volume :
- 382
- Issue :
- 6677
- Database :
- Academic Search Index
- Journal :
- Science
- Publication Type :
- Academic Journal
- Accession number :
- 174362354
- Full Text :
- https://doi.org/10.1126/science.adi9926