Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2

• 成果类型: Article
• 署名作者: Zhu, Hanwen; Tonelli, Francesca; Turk, Martin; Prescott, Alan; Alessi, Dario R.; Sun, Ji
• 署名单位: St Jude Children's Research Hospital; University of Dundee; St Jude Children's Research Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9419
• DOI: 10.1126/science.adi9926
• 发表日期: 2023-12-22
• 页码: 1404-1410
• 关键词: cryo-em structure; parkinsons-disease; gtp-binding; lrrk2; rab7l1; mutations; Visualization; validation; PATHWAY; cells

摘要

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.