A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms

Wu, Chun-XiangLiao, JinglingPark, YangshinHoang, Neo C.Engel, Victoria A.Wan, LiOh, MisookSanishvili, RuslanTakagi, YuichiroJohnson, Steven M.Wang, MuFederici, MarkNichols, R. JeremyBeilina, AlexandraReed, XylenaCookson, Mark R.Hoang, Quyen Q.2021-01-222021-01-222019Wu, C.-X., Liao, J., Park, Y., Hoang, N. C., Engel, V. A., Wan, L., Oh, M., Sanishvili, R., Takagi, Y., Johnson, S. M., Wang, M., Federici, M., Nichols, R. J., Beilina, A., Reed, X., Cookson, M. R., & Hoang, Q. Q. (2019). A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms. BioRxiv, 676627. https://doi.org/10.1101/676627https://hdl.handle.net/1805/24934Leucine-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.enAttribution-NonCommercial-NoDerivatives 4.0 InternationalLRRK2Parkinson's diseaseGTPaseA revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanismsArticle