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

• Published in: The Journal of biological chemistry 2019-04, Vol.294 (15), p.5907-5913
• Main Authors: Wu, Chun-Xiang, Liao, Jingling, Park, Yangshin, Reed, Xylena, Engel, Victoria A., Hoang, Neo C., Takagi, Yuichiro, Johnson, Steven M., Wang, Mu, Federici, Mark, Nichols, R. Jeremy, Sanishvili, Ruslan, Cookson, Mark R., Hoang, Quyen Q.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Amino Acid Substitution; conformational change; conformational dynamics; disease mutation; enzyme activation; GTPase; Guanosine Diphosphate - chemistry; Guanosine Diphosphate - genetics; Guanosine Triphosphate - chemistry; Guanosine Triphosphate - genetics; HEK293 Cells; Humans; kinase; leucine-rich repeat kinase 2 (LRRK2); Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - chemistry; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Molecular Bases of Disease; molecular dynamics; Mutation, Missense; neurodegeneration; Parkinson disease; Parkinson Disease - enzymology; Parkinson Disease - genetics; Parkinson's disease; Protein Domains; Protein Multimerization; Ras of complex proteins (ROC)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.007631

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.