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Yorodumi- PDB-8fo8: Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state -
+Open data
-Basic information
Entry | Database: PDB / ID: 8fo8 | ||||||
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Title | Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state | ||||||
Components |
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Keywords | HYDROLASE / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / Rab GTPases / Activation | ||||||
Function / homology | Function and homology information protein localization to ciliary membrane / 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 ...protein localization to ciliary membrane / 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 / PTK6 promotes HIF1A stabilization / regulation of CAMKK-AMPK signaling cascade / amphisome / cytoplasmic side of mitochondrial outer membrane / mitochondrion localization / co-receptor binding / modulation by host of viral process / intracellular vesicle / 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 / RAB geranylgeranylation / positive regulation of intracellular protein transport / multivesicular body, internal vesicle / regulation of protein kinase A signaling / striatum development / melanosome organization / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / cellular response to dopamine / cis-Golgi network / protein localization to membrane / positive regulation of protein autoubiquitination / endoplasmic reticulum organization / presynaptic cytosol / retrograde transport, endosome to Golgi / positive regulation of programmed cell death / Wnt signalosome / GTP metabolic process / cellular detoxification / regulation of canonical Wnt signaling pathway / negative regulation of protein processing / vacuole / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / negative regulation of GTPase activity / exploration behavior / MAP kinase kinase kinase activity / autolysosome / regulation of locomotion / protein kinase A binding / regulation of synaptic vesicle exocytosis / Golgi-associated vesicle / negative regulation of macroautophagy / clathrin binding / neuromuscular junction development / dynein complex binding / lysosome organization / positive regulation of receptor recycling / regulation of mitochondrial fission / intracellular distribution of mitochondria / positive regulation of T cell receptor signaling pathway / Golgi organization / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / kinesin binding / endoplasmic reticulum exit site / microvillus / Rho protein signal transduction / canonical Wnt signaling pathway / positive regulation of protein kinase activity / endomembrane system / cellular response to manganese ion / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of autophagy / neuron projection morphogenesis / JNK cascade / regulation of synaptic transmission, glutamatergic / synapse assembly / T cell activation / dendrite cytoplasm / cellular response to starvation / phosphorylation Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.88 Å | ||||||
Authors | Zhu, H. / Sun, J. | ||||||
Funding support | United States, 1items
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Citation | Journal: Science / Year: 2023 Title: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. Authors: Hanwen Zhu / Francesca Tonelli / Martin Turk / Alan Prescott / Dario R Alessi / Ji Sun / Abstract: Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles ...Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment. #1: Journal: bioRxiv / Year: 2022 Title: Structural basis of human LRRK2 membrane recruitment and activation Authors: Zhu, H. / Tonelli, F. / Alessi, D. / Sun, J. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8fo8.cif.gz | 820.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8fo8.ent.gz | 655.5 KB | Display | PDB format |
PDBx/mmJSON format | 8fo8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8fo8_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8fo8_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 8fo8_validation.xml.gz | 131.9 KB | Display | |
Data in CIF | 8fo8_validation.cif.gz | 201.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fo/8fo8 ftp://data.pdbj.org/pub/pdb/validation_reports/fo/8fo8 | HTTPS FTP |
-Related structure data
Related structure data | 29341MC 8fo2C 8fo9C 8smcC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 20239.076 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: RAB29, RAB7L1 / Production host: Escherichia coli (E. coli) / References: UniProt: O14966 #2: Protein | Mass: 286427.656 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK2, PARK8 / Production host: Homo sapiens (human) References: UniProt: Q5S007, non-specific serine/threonine protein kinase, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement #3: Chemical | #4: Chemical | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Rab29-LRRK2 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm |
Image recording | Electron dose: 58.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
EM software |
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CTF correction | Type: NONE | |||||||||
3D reconstruction | Resolution: 3.88 Å / Resolution method: OTHER / Num. of particles: 96502 / Symmetry type: POINT |