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- PDB-7li3: Structure of the LRRK2 G2019S mutant -

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Basic information

Entry
Database: PDB / ID: 7li3
TitleStructure of the LRRK2 G2019S mutant
ComponentsLeucine-rich repeat serine/threonine-protein kinase 2
KeywordsTRANSFERASE / HYDROLASE / Parkinson's disease / microtubule / kinase / cryo-EM / NEUROPEPTIDE
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 / positive regulation of dopamine receptor signaling pathway / negative regulation of protein targeting to mitochondrion / regulation of lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / amphisome / mitochondrion localization / cytoplasmic side of mitochondrial outer membrane / multivesicular body, internal vesicle / co-receptor binding / regulation of retrograde transport, endosome to Golgi / negative regulation of excitatory postsynaptic potential / negative regulation of autophagosome assembly / regulation of dopamine receptor signaling pathway / 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 dendritic spine morphogenesis / regulation of protein kinase A signaling / striatum development / protein localization to mitochondrion / cellular response to dopamine / presynaptic cytosol / positive regulation of protein autoubiquitination / endoplasmic reticulum organization / Wnt signalosome / GTP metabolic process / regulation of canonical Wnt signaling pathway / positive regulation of programmed cell death / negative regulation of protein processing / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / exploration behavior / negative regulation of GTPase activity / protein kinase A binding / regulation of locomotion / autolysosome / regulation of synaptic vesicle exocytosis / Golgi-associated vesicle / PTK6 promotes HIF1A stabilization / clathrin binding / negative regulation of macroautophagy / lysosome organization / neuromuscular junction development / regulation of mitochondrial fission / locomotory exploration behavior / intracellular distribution of mitochondria / Golgi organization / positive regulation of nitric-oxide synthase biosynthetic process / microvillus / Rho protein signal transduction / cellular response to organic cyclic compound / MAP kinase kinase kinase activity / canonical Wnt signaling pathway / positive regulation of protein kinase activity / cellular response to manganese ion / endoplasmic reticulum exit site / 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 / mitochondrion organization / cellular response to starvation / regulation of membrane potential / dendrite cytoplasm / GTPase activator activity / tubulin binding / SNARE binding / neuron projection morphogenesis / negative regulation of protein phosphorylation / negative regulation of protein binding / positive regulation of protein ubiquitination / regulation of autophagy / determination of adult lifespan / calcium-mediated signaling / mitochondrial membrane / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / peptidyl-threonine phosphorylation / regulation of protein stability / positive regulation of MAP kinase activity / 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
ADENOSINE-5'-TRIPHOSPHATE / GUANOSINE-5'-DIPHOSPHATE / Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsMyasnikov, A. / Zhu, H. / Hixson, P. / Xie, B. / Yu, K. / Pitre, A. / Peng, J. / Sun, J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA)HL143037(JS) United States
National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA)AG053987 (JP) United States
CitationJournal: Cell / Year: 2021
Title: Structural analysis of the full-length human LRRK2.
Authors: Alexander Myasnikov / Hanwen Zhu / Patricia Hixson / Boer Xie / Kaiwen Yu / Aaron Pitre / Junmin Peng / Ji Sun /
Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 regulates critical cellular processes at ...Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 regulates critical cellular processes at membranous organelles and forms microtubule-based pathogenic filaments, yet the molecular basis underlying these biological roles of LRRK2 remains largely enigmatic. Here, we determined high-resolution structures of full-length human LRRK2, revealing its architecture and key interdomain scaffolding elements for rationalizing disease-causing mutations. The kinase domain of LRRK2 is captured in an inactive state, a conformation also adopted by the most common PD-associated mutation, LRRK2. This conformation serves as a framework for structure-guided design of conformational specific inhibitors. We further determined the structure of COR-mediated LRRK2 dimers and found that single-point mutations at the dimer interface abolished pathogenic filamentation in cells. Overall, our study provides mechanistic insights into physiological and pathological roles of LRRK2 and establishes a structural template for future therapeutic intervention in PD.
History
DepositionJan 26, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
A: Leucine-rich repeat serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)287,4083
Polymers286,4581
Non-polymers9502
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1400 Å2
ΔGint-8 kcal/mol
Surface area79980 Å2

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Components

#1: Protein Leucine-rich repeat serine/threonine-protein kinase 2 / Dardarin


Mass: 286457.688 Da / Num. of mol.: 1 / Mutation: G2019S variant
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
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: LRRK2 G2019S mutant / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 81 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM software
IDNameVersionCategory
4Gctf1.06CTF correction
10cryoSPARC3.01initial Euler assignment
11cryoSPARC3.01final Euler assignment
13cryoSPARC3.013D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 81046 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00414449
ELECTRON MICROSCOPYf_angle_d0.66819556
ELECTRON MICROSCOPYf_dihedral_angle_d27.0891935
ELECTRON MICROSCOPYf_chiral_restr0.0452274
ELECTRON MICROSCOPYf_plane_restr0.0042457

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