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

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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.

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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This work was supported by National Institutes of Health Grants R01GM111639 and R01GM115844 and the Michael J. Fox Foundation(to Q. Q. H.), Grant R01GM111695 and U.S. National Science Foundation Grant MCB-1157688 (to Y. T.), the Intramural Research Program of the National Institutes of Health, National Institute on Aging (to M. R. C.), National Institutes of Health Grant R01GM120350 (to S. M. J.), and funding from the Travel and Learn program of the Indiana Association of Chinese-Americans (IACA) (to N. C. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Both authors contributed equally to this work.

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The abbreviations used are:

    LRRK2

    leucine-rich repeat kinase 2

    PD

    Parkinson's disease

    ROS

    Ras of complex proteins

    COR

    C-terminal of ROC

    Kin

    kinase domain

    SEC-MALS

    multiangle light scattering coupled to size-exclusion chromatography

    Gpp(NH)p

    guanosine 5′-(β,γ-imido)triphosphate.