The Parkinson’s disease–associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2

Xiaorong Huang, Chunxiang Wu, Yangshin Park, Xuwei Long, Quyen Q. Hoang, Jingling Liao

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Parkinson disease–associated mutations within the GTPase domain Ras of complex proteins (ROC) of leucine rich repeat kinase 2 (LRRK2) result in an abnormal over-activation of its kinase domain. However, the mechanisms involved remain unclear. Recent study has shown that LRRK2 G-domain cycles between monomeric and dimeric conformations upon binding to GTP or guanosine diphosphate, and that the Parkinson’s disease (PD)associated R1441C/G/H mutations impair the G-domain monomer-dimer dynamics and trap the G-domain in a constitutive monomeric conformation. That led us to question whether other disease-associated mutations in G-domain would also affect its conformation. Here, we report that another PD-associated N1437H mutation also impairs its monomer-dimer conformational dynamics and GTPase activity. In contrast with mutations at R1441, ROCN1437H was found to be locked in a stable dimeric conformation in solution and its GTPase activity was ∼4-fold lower than that of the wild-type. Furthermore, the N1437H mutation reduced the GTP binding affinity by ∼2.5-fold when compared with other pathogenic G-domain mutations. Moreover, ROCN1437H was found to have a slower GTP dissociation rate, indicating that N1437H might interrupt the nucleotide exchange cycle. Taken together, our data support that conformational dynamics is important for LRRK2 GTPase activity and that the N1437H mutation impairs GTPase activity by locking the ROC domain in a persistently dimeric state.

Original languageEnglish (US)
Pages (from-to)4814-4823
Number of pages10
JournalFASEB Journal
Volume33
Issue number4
DOIs
StatePublished - 2019

Keywords

  • Disease-associated mutation
  • GTPase activity
  • Monomer-dimer

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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