6XR4

Integrative in situ structure of Parkinsons disease-linked human LRRK2

Summary for 6XR4

• Entry DOI: 10.2210/pdb6xr4/pdb
• EMDB information: 20825 20826 20827 20828
• Descriptor: Leucine-rich repeat serine/threonine-protein kinase 2 (1 entity in total)
• Functional Keywords: kinase, gtpase, parkinson's disease, pseudo-kinase, signaling protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 572901.44

Authors

Villa, E.,Lasker, K.,Audagnotto, M. (deposition date: 2020-07-10, release date: 2020-08-19, Last modification date: 2024-03-06)

Primary citation

Watanabe, R.,Buschauer, R.,Bohning, J.,Audagnotto, M.,Lasker, K.,Lu, T.W.,Boassa, D.,Taylor, S.,Villa, E.
The In Situ Structure of Parkinson's Disease-Linked LRRK2.
Cell, 182:1508-, 2020

PubMed Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease. LRRK2 is a multi-domain protein containing a kinase and GTPase. Using correlative light and electron microscopy, in situ cryo-electron tomography, and subtomogram analysis, we reveal a 14-Å structure of LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double helix around microtubules, which are left-handed. Using integrative modeling, we determine the architecture of LRRK2, showing that the GTPase and kinase are in close proximity, with the GTPase closer to the microtubule surface, whereas the kinase is exposed to the cytoplasm. We identify two oligomerization interfaces mediated by non-catalytic domains. Mutation of one of these abolishes LRRK2 microtubule-association. Our work demonstrates the power of cryo-electron tomography to generate models of previously unsolved structures in their cellular environment.

PubMed: 32783917
DOI: 10.1016/j.cell.2020.08.004

Experimental method

ELECTRON MICROSCOPY (14 Å)