- EMDB-21250: Cryo-EM structure of the C-terminal half of the Parkinson's Disea... -
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Basic information
Entry
Database: EMDB / ID: EMD-21250
Title
Cryo-EM structure of the C-terminal half of the Parkinson's Disease-linked protein Leucine Rich Repeat Kinase 2 (LRRK2)
Map data
3.8A signal subtracted locally filtered cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 (LRRK2)
Sample
Complex: The C-terminal half of the Leucine Rich Repeat Kinase 2 (LRRK2) protein.
Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
Ligand: GUANOSINE-5'-DIPHOSPHATE
Ligand: MAGNESIUM ION
Function / homology
Function and homology information
peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / tangential migration from the subventricular zone to the olfactory bulb ...peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / negative regulation of late endosome to lysosome transport / regulation of synaptic vesicle transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / positive regulation of dopamine receptor signaling pathway / regulation of lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / amphisome / mitochondrion localization / cytoplasmic side of mitochondrial outer membrane / co-receptor binding / regulation of retrograde transport, endosome to Golgi / negative regulation of excitatory postsynaptic potential / regulation of dopamine receptor signaling pathway / negative regulation of autophagosome assembly / positive regulation of microglial cell activation / neuron projection arborization / positive regulation of synaptic vesicle endocytosis / JUN kinase kinase kinase activity / olfactory bulb development / regulation of protein kinase A signaling / multivesicular body, internal vesicle / striatum development / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / cellular response to dopamine / presynaptic cytosol / positive regulation of protein autoubiquitination / endoplasmic reticulum organization / positive regulation of programmed cell death / Wnt signalosome / regulation of canonical Wnt signaling pathway / GTP metabolic process / negative regulation of protein processing / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / negative regulation of GTPase activity / exploration behavior / protein kinase A binding / autolysosome / regulation of locomotion / Golgi-associated vesicle / neuromuscular junction development / regulation of synaptic vesicle exocytosis / PTK6 promotes HIF1A stabilization / clathrin binding / negative regulation of macroautophagy / regulation of mitochondrial fission / intracellular distribution of mitochondria / lysosome organization / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / Golgi organization / endoplasmic reticulum exit site / microvillus / Rho protein signal transduction / MAP kinase kinase kinase activity / positive regulation of protein kinase activity / canonical Wnt signaling pathway / cellular response to manganese ion / positive regulation of autophagy / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / JNK cascade / regulation of synaptic transmission, glutamatergic / excitatory postsynaptic potential / dendrite cytoplasm / cellular response to starvation / tubulin binding / mitochondrion organization / GTPase activator activity / neuron projection morphogenesis / SNARE binding / negative regulation of protein phosphorylation / negative regulation of protein binding / regulation of autophagy / positive regulation of protein ubiquitination / regulation of membrane potential / determination of adult lifespan / mitochondrial membrane / calcium-mediated signaling / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / peptidyl-threonine phosphorylation / positive regulation of MAP kinase activity / regulation of protein stability / protein localization / trans-Golgi network Similarity search - Function
C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. ...C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Rab subfamily of small GTPases / Leucine-rich repeat domain superfamily / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Small GTP-binding protein domain / Armadillo-type fold / WD40-repeat-containing domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase Similarity search - Domain/homology
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM107214
United States
Michael J. Fox Foundation
11425.02
United States
Citation
Journal: Nature / Year: 2020 Title: Structure of LRRK2 in Parkinson's disease and model for microtubule interaction. Authors: C 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 / Abstract: 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 ...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.
History
Deposition
Jan 29, 2020
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Header (metadata) release
Aug 26, 2020
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Map release
Aug 26, 2020
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Update
Dec 23, 2020
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Current status
Dec 23, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK II
Details
4uM concentration
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Electron microscopy
Microscope
FEI TITAN KRIOS
Specialist optics
Energy filter - Name: GIF 2002
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 3826 / Average exposure time: 8.0 sec. / Average electron dose: 6.65 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Type of model: OTHER Details: Generated initial models from ab initio refinement in Cryosparc.
Final reconstruction
Applied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software:
Name
details
RELION (ver. 3)
C1
cryoSPARC (ver. 2)
C3
Details: For the signal subtracted map, 105,787 (tripled) particles went into the final map that achieved 3.8A resolution. Number images used: 70953
Initial angle assignment
Type: MAXIMUM LIKELIHOOD / Software: (Name: RELION (ver. 3), cryoSPARC (ver. 2)) Details: Signal subtracted map was generated in Relion3. The C3 map however was created in Cryosparc 2.
Final angle assignment
Type: MAXIMUM LIKELIHOOD / Software: (Name: RELION (ver. 3), cryoSPARC (ver. 2)) Details: Signal subtracted map was generated in Relion3. The C3 map however was created in Cryosparc 2.
FSC plot (resolution estimation)
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