Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 15, Pages 5907-5913Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.007631
Keywords
leucine-rich repeat kinase 2 (LRRK2); Parkinson disease; GTPase; conformational change; molecular dynamics; conformational dynamics; disease mutation; enzyme activation; kinase; Ras of complex proteins (ROC)
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Funding
- National Institutes of Health [R01GM111639, R01GM115844, R01GM120350]
- Michael J. Fox Foundation [R01GM111695]
- U.S. National Science Foundation [MCB-1157688]
- Intramural Research Program of the National Institutes of Health, National Institute on Aging
- Travel and Learn program of the Indiana Association of Chinese-Americans (IACA)
- NATIONAL INSTITUTE ON AGING [ZIAAG000937] Funding Source: NIH RePORTER
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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.
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