The In Situ Structure of Parkinson's Disease-Linked LRRK2.
Cell
; 182(6): 1508-1518.e16, 2020 09 17.
Article
in En
| MEDLINE
| ID: mdl-32783917
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Parkinson Disease
/
Cryoelectron Microscopy
/
Electron Microscope Tomography
/
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/
Microtubules
Limits:
Humans
Language:
En
Journal:
Cell
Year:
2020
Type:
Article
Affiliation country:
United States