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 Johnson, Mu Wang, Mark Federici, R. Jeremy Nichols, Ruslan Sanishvili, Mark R. Cookson, Quyen Hoang

Research output: Contribution to journalArticle

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 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 (US)
Pages (from-to)5907-5913
Number of pages7
JournalJournal of Biological Chemistry
Volume294
Issue number15
DOIs
StatePublished - Jan 1 2019

Fingerprint

GTP Phosphohydrolases
ras Proteins
Leucine
Parkinson Disease
Conformations
Phosphotransferases
Nucleotides
Mutation
Guanosine Triphosphate
Proteins
Dimers
Substitution reactions
Monomers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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; Wang, Mu; Federici, Mark; Jeremy Nichols, R.; Sanishvili, Ruslan; Cookson, Mark R.; Hoang, Quyen.

In: Journal of Biological Chemistry, Vol. 294, No. 15, 01.01.2019, p. 5907-5913.

Research output: Contribution to journalArticle

Wu, Chun Xiang ; Liao, Jingling ; Park, Yangshin ; Reed, Xylena ; Engel, Victoria A. ; Hoang, Neo C. ; Takagi, Yuichiro ; Johnson, Steven ; Wang, Mu ; Federici, Mark ; Jeremy Nichols, R. ; Sanishvili, Ruslan ; Cookson, Mark R. ; Hoang, Quyen. / Parkinson’s disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 15. pp. 5907-5913.
@article{6c5d966abbb94db097716240988c308c,
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 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.",
author = "Wu, {Chun Xiang} and Jingling Liao and Yangshin Park and Xylena Reed and Engel, {Victoria A.} and Hoang, {Neo C.} and Yuichiro Takagi and Steven Johnson and Mu Wang and Mark Federici and {Jeremy Nichols}, R. and Ruslan Sanishvili and Cookson, {Mark R.} and Quyen Hoang",
year = "2019",
month = "1",
day = "1",
doi = "10.1074/jbc.RA119.007631",
language = "English (US)",
volume = "294",
pages = "5907--5913",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "15",

}

TY - JOUR

T1 - Parkinson’s disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics

AU - Wu, Chun Xiang

AU - Liao, Jingling

AU - Park, Yangshin

AU - Reed, Xylena

AU - Engel, Victoria A.

AU - Hoang, Neo C.

AU - Takagi, Yuichiro

AU - Johnson, Steven

AU - Wang, Mu

AU - Federici, Mark

AU - Jeremy Nichols, R.

AU - Sanishvili, Ruslan

AU - Cookson, Mark R.

AU - Hoang, Quyen

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85064338742&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064338742&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA119.007631

DO - 10.1074/jbc.RA119.007631

M3 - Article

C2 - 30796162

AN - SCOPUS:85064338742

VL - 294

SP - 5907

EP - 5913

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 15

ER -