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| Title | Structural basis for Parkinson's disease-linked LRRK2's binding to microtubules. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Vol. 29, Issue 12, Page 1196-1207, Year 2022 |
| Publish date | Dec 12, 2022 |
 Authors | David M Snead / Mariusz Matyszewski / Andrea M Dickey / Yu Xuan Lin / Andres E Leschziner / Samara L Reck-Peterson /  |
| PubMed Abstract | Leucine-rich repeat kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson's disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an ...Leucine-rich repeat kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson's disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-EM structure of the catalytic half of LRRK2, containing its kinase, in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2 but is not linked to PD. Although LRRK1's structure is similar to that of LRRK2, we find that LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2's GTPase that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2's kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors. |
 External links | Nat Struct Mol Biol / PubMed:36510024 / PubMed Central |
| Methods | EM (helical sym.) / EM (single particle) |
| Resolution | 4.5 - 18.0 Å |
| Structure data |  EMDB-25649: Helical Reconstruction of the C-terminal Half of Leucine Rich Repeat Kinase 2 (LRRK2) (I2020T) bound to 11-protofilament microtubule in presence of MLi-2 kinase inhibitor  EMDB-25658: Local refinement of the C-terminal Half of Leucine Rich Repeat Kinase 2 (LRRK2) (I2020T) bound to 11-protofilament microtubule in presence of MLi-2 kinase inhibitor  EMDB-25664: Local Refinement of the C-terminal Half of Leucine Rich Repeat Kinase 2 (LRRK2) (I2020T) tetramer bound to 11-protofilament microtubule in presence of MLi-2 kinase inhibitor  EMDB-25672: Structure of the C-terminal half of Leucine Rich Repeat Kinase 1 (LRRK1)  EMDB-25674: Local refinement of the C-terminal Half of Leucine Rich Repeat Kinase 2 (LRRK2) (I2020T) bound to 12-protofilament microtubule without kinase inhibitors present  EMDB-25897: Local refinement of the C-terminal Half of Leucine Rich Repeat Kinase 2 (LRRK2) (I2020T) bound to 11-protofilament microtubule focused on the monomer in presence of MLi-2 kinase inhibitor EMDB-25906, PDB-7thy: EMDB-25907, PDB-7thz:  EMDB-25908: 2 microtubule protofilaments locally refined from Leucine Rich Repeat Kinase 2 filament structure bound to 11-protofilament microtubules |
| Chemicals |  ChemComp-GDP: |
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 Keywords |  CYTOSOLIC PROTEIN / parkinson's disease / microtubule / kinase / gtpase |
