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

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.

doi:10.1074/jbc.RA119.007631

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

Journal Article · 21 February 2019 · Journal of Biological Chemistry

DOI: https://doi.org/10.1074/jbc.RA119.007631 · OSTI ID:1571497

Wu, Chun-Xiang ^[1]; Liao, Jingling ^[2]; Park, Yangshin ^[1]; Reed, Xylena ^[3]; Engel, Victoria A. ^[1]; Hoang, Neo C. ^[1]; Takagi, Yuichiro ^[4];

^[4]; Wang, Mu ^[5]; Federici, Mark ^[6]; Nichols, R. Jeremy ^[7]; Sanishvili, Ruslan ^[8];

^[3]; Hoang, Quyen Q. ^[9]

Indiana Univ. School of Medicine, Indianapolis, IN (United States). Dept. of Biochemistry and Molecular Biology; Indiana Univ. School of Medicine, Indianapolis, IN (United States). The Stark Neurosciences Inst.
Indiana Univ. School of Medicine, Indianapolis, IN (United States). Dept. of Biochemistry and Molecular Biology; Indiana Univ. School of Medicine, Indianapolis, IN (United States). The Stark Neurosciences Inst.; Wuhan Univ. of Science and Technology School of Medicine, Wuhan (China). Dept. of Public Health
National Inst. of Health, Bethesda, MD (United States). Lab. of Neurogenetics
Indiana Univ. School of Medicine, Indianapolis, IN (United States). Dept. of Biochemistry and Molecular Biology
Indiana Univ. School of Medicine, Indianapolis, IN (United States). Dept. of Biochemistry and Molecular Biology; Xi'an Jiaotong-Liverpool Univ., Suzhou, Jiangsu (China). Dept. of Biological Sciences
ThermoFisher Scientific, Carlsbad (California)
Stanford Univ., Stanford, CA (United States). Dept. of Pathology
Argonne National Lab. (ANL), Argonne, IL (United States). X-ray Sciences Division
Indiana Univ. School of Medicine, Indianapolis, IN (United States). Dept. of Biochemistry and Molecular Biology and Neurology; Indiana Univ. School of Medicine, Indianapolis, IN (United States). The Stark Neurosciences Inst.

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 ROC domain of LRRK2 exists in a dynamic dimermonomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the diseaseassociated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTPbound- like monomeric conformation. Moreover, we show that residue arginine 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 monomerdimer dynamics and thereby trap its GTPase domain in an activated state.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Science Foundation (NSF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1571497

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 15 Vol. 294; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

References (21)

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60 APPLIED LIFE SCIENCES
GTPase
Parkinson's disease
Ras of complex proteins (ROC)
conformational dynamics
disease mutation
enzyme activation
kinase
leucine-rich repeat kinase 2 (LRRK2)
neurodegeneration

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

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