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

Science. 2023 Dec 22;382(6677):1404-1411. doi: 10.1126/science.adi9926. Epub 2023 Dec 21.

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.

MeSH terms

  • Antiparkinson Agents / chemistry
  • Antiparkinson Agents / pharmacology
  • Catalytic Domain
  • Cryoelectron Microscopy
  • Drug Design
  • Gain of Function Mutation
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / antagonists & inhibitors
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / chemistry
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / genetics
  • Parkinson Disease* / drug therapy
  • Parkinson Disease* / genetics
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Multimerization
  • Protein Subunits / chemistry
  • rab GTP-Binding Proteins* / chemistry

Substances

  • Antiparkinson Agents
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Subunits
  • rab GTP-Binding Proteins
  • Rab29 protein, human
  • Protein Kinase Inhibitors

Supplementary concepts

  • Parkinson Disease 16