Parkinson’s disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics

Chun Xiang Wu, Jingling Liao, Yangshin Park, Xylena Reed, Victoria A. Engel, Neo C. Hoang, Yuichiro Takagi, Steven M. Johnson, Mu Wang, Mark Federici, R. Jeremy Nichols, Ruslan Sanishvili, Mark R. Cookson, Quyen Q. Hoang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


Mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson’s disease (PD). Recently, we showed that a disease-associated mutation R1441H rendered the GTPase domain of LRRK2 catalytically less active and thereby trapping it in a more persistently “on” conformation. However, the mechanism involved and characteristics of this on conformation remained unknown. Here, we report that the Ras of complex protein (ROC) domain of LRRK2 exists in a dynamic dimer–monomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the PD-associated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTP-bound–like monomeric conformation. Moreover, we show that residue Arg-1441 is critical for regulating the conformational dynamics of ROC. In summary, our results reveal that the PD-associated substitutions at Arg-1441 of LRRK2 alter monomer– dimer dynamics and thereby trap its GTPase domain in an activated state.

Original languageEnglish
Pages (from-to)5907-5913
Number of pages7
JournalJournal of Biological Chemistry
Issue number15
Publication statusPublished - 12 Apr 2019

Cite this