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

The Journal of Biological Chemistry
Chun-Xiang WuQuyen Q Hoang

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.

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Citations

Apr 23, 2020·Frontiers in Neuroscience·Jascha T ManschwetusFriedrich W Herberg
Oct 21, 2020·Biochemical Society Transactions·Ahmed SolimanArjan Kortholt
Feb 3, 2021·Molecular and Cellular Biology·Ahsan UsmaniAnnie Hiniker
May 26, 2021·Molecular Neurodegeneration·Souvarish SarkarMel B Feany
Sep 10, 2021·ACS Chemical Biology·Leah G HeltonEileen J Kennedy

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