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Structure paper

TitleStructure of LRRK2 in Parkinson's disease and model for microtubule interaction.
Journal, issue, pagesNature, Vol. 588, Issue 7837, Page 344-349, Year 2020
Publish dateAug 19, 2020
AuthorsC K Deniston / J Salogiannis / S Mathea / D M Snead / I Lahiri / M Matyszewski / O Donosa / R Watanabe / J Böhning / A K Shiau / S Knapp / E Villa / S L Reck-Peterson / A E Leschziner /
PubMed AbstractLeucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease and is also linked to its idiopathic form. LRRK2 has been proposed to function in membrane ...Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease and is also linked to its idiopathic form. LRRK2 has been proposed to function in membrane trafficking and colocalizes with microtubules. Despite the fundamental importance of LRRK2 for understanding and treating Parkinson's disease, structural information on the enzyme is limited. Here we report the structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported cryo-electron tomography in situ structure. We propose that the conformation of the LRRK2 kinase domain regulates its interactions with microtubules, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin 1 and cytoplasmic dynein 1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce the formation of LRRK2 filaments in cells, whereas inhibitors that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.
External linksNature / PubMed:32814344 / PubMed Central
MethodsEM (single particle)
Resolution3.47 - 13.4 Å
Structure data

21250

6vno

6vp6

6vp7

6vp8

EMDB-21250, PDB-6vno, PDB-6vp6, PDB-6vp7, PDB-6vp8:
Cryo-EM structure of the C-terminal half of the Parkinson's Disease-linked protein Leucine Rich Repeat Kinase 2 (LRRK2)
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-21306:
Cryo-EM map of the C-terminal half of Leucine Rich Repeat Kinase 2 as a monomer at 8.1 angstroms
Method: EM (single particle) / Resolution: 8.1 Å

EMDB-21309:
Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a COR-COR domain dimer at 9.5 angstroms
Method: EM (single particle) / Resolution: 9.5 Å

EMDB-21310:
Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a WD40-WD40 domain dimer at 13.4 angstroms
Method: EM (single particle) / Resolution: 13.4 Å

EMDB-21311:
Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a COR-COR domain dimer in the presence of the MLi-2 kinase inhibitor at 9.0 angstroms
Method: EM (single particle) / Resolution: 9.0 Å

EMDB-21312:
Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a WD40-WD40 domain dimer in the presence of the MLi-2 kinase inhibitor at 10.2 angstroms
Method: EM (single particle) / Resolution: 10.2 Å

Chemicals

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Kinase / GTPase

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