Browsing by Author "Beilina, Alexandra"

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    A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms
    (Cold Spring Harbor Laboratory Press, 2019) Wu, Chun-Xiang; Liao, Jingling; Park, Yangshin; Hoang, Neo C.; Engel, Victoria A.; Wan, Li; Oh, Misook; Sanishvili, Ruslan; Takagi, Yuichiro; Johnson, Steven M.; Wang, Mu; Federici, Mark; Nichols, R. Jeremy; Beilina, Alexandra; Reed, Xylena; Cookson, Mark R.; Hoang, Quyen Q.; Biochemistry and Molecular Biology, School of Medicine
    Leucine-rich repeat kinase 2 (LRRK2) is a large 286 kDa multi-domain protein whose mutation is a common cause of Parkinson’s disease (PD). One of the common sites of familial PD-associated mutations occurs at residue Arg-1441 in the GTPase domain of LRRK2. Previously, we reported that the PD-associated mutation R1441H impairs the catalytic activity of the GTPase domain thereby traps it in a persistently "on" state. More recently, we reported that the GTPase domain of LRRK2 exists in a dynamic dimer-monomer equilibrium where GTP binding shifts it to the monomeric conformation while GDP binding shifts it back to the dimeric state. We also reported that all of the PD-associated mutations at Arg-1441, including R1441H, R1441C, and R1441G, impair the nucleotide-dependent dimer-monomer conformational dynamics of the GTPase domain. However, the mechanism of this nucleotide-dependent conformational dynamics and how it is impaired by the mutations at residue Arg-1441 remained unclear. Here, we report a 1.6 Å crystal structure of the GTPase domain of LRRK2. Our structure has revealed a dynamic switch region that can be differentially regulated by GTP and GDP binding. This nucleotide-dependent regulation is impaired when residue Arg-1441 is substituted with the PD-associated mutations due to the loss of its exquisite interactions consisting of two hydrogen bonds and a π-stacking interaction at the dimer interface.