A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms
dc.contributor.author | Wu, Chun-Xiang | |
dc.contributor.author | Liao, Jingling | |
dc.contributor.author | Park, Yangshin | |
dc.contributor.author | Hoang, Neo C. | |
dc.contributor.author | Engel, Victoria A. | |
dc.contributor.author | Wan, Li | |
dc.contributor.author | Oh, Misook | |
dc.contributor.author | Sanishvili, Ruslan | |
dc.contributor.author | Takagi, Yuichiro | |
dc.contributor.author | Johnson, Steven M. | |
dc.contributor.author | Wang, Mu | |
dc.contributor.author | Federici, Mark | |
dc.contributor.author | Nichols, R. Jeremy | |
dc.contributor.author | Beilina, Alexandra | |
dc.contributor.author | Reed, Xylena | |
dc.contributor.author | Cookson, Mark R. | |
dc.contributor.author | Hoang, Quyen Q. | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | en_US |
dc.date.accessioned | 2021-01-22T21:19:02Z | |
dc.date.available | 2021-01-22T21:19:02Z | |
dc.date.issued | 2019 | |
dc.description.abstract | 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. | en_US |
dc.eprint.version | Final published version | en_US |
dc.identifier.citation | Wu, 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/10.1101/676627 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/24934 | |
dc.language.iso | en | en_US |
dc.publisher | Cold Spring Harbor Laboratory Press | en_US |
dc.relation.isversionof | 10.1101/676627 | en_US |
dc.relation.journal | BioRxiv | en_US |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.source | Publisher | en_US |
dc.subject | LRRK2 | en_US |
dc.subject | Parkinson's disease | en_US |
dc.subject | GTPase | en_US |
dc.title | A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms | en_US |
dc.type | Article | en_US |