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-Structure paper
Title | Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. |
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Journal, issue, pages | Science, Vol. 382, Issue 6677, Page 1404-1411, Year 2023 |
Publish date | Dec 22, 2023 |
Authors | Hanwen Zhu / Francesca Tonelli / Martin Turk / Alan Prescott / Dario R Alessi / Ji Sun / |
PubMed Abstract | Gain-of-function mutations in , 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 ...Gain-of-function mutations in , 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 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. |
External links | Science / PubMed:38127736 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.48 - 4.13 Å |
Structure data | EMDB-29339, PDB-8fo2: EMDB-29341, PDB-8fo8: EMDB-29342, PDB-8fo9: EMDB-40588, PDB-8smc: |
Chemicals | ChemComp-MG: ChemComp-GNP: ChemComp-GDP: ChemComp-ATP: ChemComp-TVT: |
Source |
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Keywords | HYDROLASE / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / Rab GTPases / Activation |