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

Abstract

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.

Authors:
 [1];  [2];  [1];  [3];  [1];  [1];  [4]; ORCiD logo [4];  [5];  [6];  [7];  [8]; ORCiD logo [3];  [9]
+ Show Author Affiliations
  1. 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.
  2. 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
  3. National Inst. of Health, Bethesda, MD (United States). Lab. of Neurogenetics
  4. Indiana Univ. School of Medicine, Indianapolis, IN (United States). Dept. of Biochemistry and Molecular Biology;
  5. 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
  6. ThermoFisher Scientific, Carlsbad (California)
  7. Stanford Univ., Stanford, CA (United States). Dept. of Pathology
  8. Argonne National Lab. (ANL), Argonne, IL (United States). X-ray Sciences Division
  9. 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.
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Science Foundation (NSF)
OSTI Identifier:
1571497
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 294; Journal Issue: 15; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
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

Citation Formats

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., and Hoang, Quyen Q.. Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics. United States: N. p., 2019. Web. doi:10.1074/jbc.RA119.007631.
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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.. Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics. United States. https://doi.org/10.1074/jbc.RA119.007631
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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., and Hoang, Quyen Q.. Fri . "Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics". United States. https://doi.org/10.1074/jbc.RA119.007631. https://www.osti.gov/servlets/purl/1571497.
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@article{osti_1571497,
title = {Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics},
author = {Wu, Chun-Xiang and Liao, Jingling and Park, Yangshin and Reed, Xylena and Engel, Victoria A. and Hoang, Neo C. and Takagi, Yuichiro and Johnson, Steven M. and Wang, Mu and Federici, Mark and Nichols, R. Jeremy and Sanishvili, Ruslan and Cookson, Mark R. and Hoang, Quyen Q.},
abstractNote = {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.},
doi = {10.1074/jbc.RA119.007631},
journal = {Journal of Biological Chemistry},
number = 15,
volume = 294,
place = {United States},
year = {2019},
month = {2}
}
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https://doi.org/10.1074/jbc.RA119.007631
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Works referenced in this record:

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