Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38127736.
- Also identified by DOI 10.1126/science.adi9926 and PMC identifier 10786121.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Gain-of-function mutations in <i>LRRK2</i>, 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 <i>PARK16</i> 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.
Medical subject headings
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
- Parkinson Disease
- rab GTP-Binding Proteins