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

  • Science. 2023 Dec 22;382(6677):1404-1411. doi: 10.1126/science.adi9926.
Hanwen Zhu  #  1 ,  Francesca Tonelli  #  2  3 ,  Martin Turk  4 ,  Alan Prescott  2 ,  Dario R Alessi  2  3 ,  Ji Sun  1
Affiliations
  • 1. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 2. MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
  • 3. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • 4. Cryo-EM and Tomography Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • # Contributed equally.
PMID: 38127736 DOI: 10.1126/science.adi9926
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.