PT  - JOURNAL ARTICLE
AU  - Reika Watanabe
AU  - Robert Buschauer
AU  - Jan Böhning
AU  - Martina Audagnotto
AU  - Keren Lasker
AU  - Tsan Wen Lu
AU  - Daniela Boassa
AU  - Susan Taylor
AU  - Elizabeth Villa
TI  - The <em>in situ</em> structure of Parkinson’s disease-linked LRRK2
AID  - 10.1101/837203
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 837203
4099  - http://biorxiv.org/content/early/2019/11/10/837203.short
4100  - http://biorxiv.org/content/early/2019/11/10/837203.full
AB  - 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 in situ cryo-electron tomography and subtomogram averaging, 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 points towards the microtubule, while 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 obtain structures of previously unsolved proteins in their cellular environment and provides insights into LRRK2 function and pathogenicity.