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- PDB-8e05: Structure of dimeric LRRK1 -

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Basic information

Entry
Database: PDB / ID: 800000
TitleStructure of dimeric LRRK1
ComponentsLeucine-rich repeat serine/threonine-protein kinase 1
KeywordsTRANSFERASE / dimer
Function / homology
Function and homology information


osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of canonical Wnt signaling pathway / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity ...osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of canonical Wnt signaling pathway / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / intracellular signal transduction / protein serine kinase activity / protein serine/threonine kinase activity / GTP binding / mitochondrion / ATP binding / metal ion binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
: / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine Rich Repeat / Leucine-rich repeats, bacterial type / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily ...: / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine Rich Repeat / Leucine-rich repeats, bacterial type / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Leucine-rich repeat domain superfamily / Ankyrin repeat-containing domain superfamily / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Leucine-rich repeat serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsReimer, J.M. / Lin, Y.X. / Leschziner, A.E.
Funding support United States, 4items
OrganizationGrant numberCountry
Damon Runyon Cancer Research FoundationDRG-2370-19 United States
Michael J. Fox Foundation18321 United States
Other privateASAP-000519
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM107214 United States
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Structure of LRRK1 and mechanisms of autoinhibition and activation.
Authors: Janice M Reimer / Andrea M Dickey / Yu Xuan Lin / Robert G Abrisch / Sebastian Mathea / Deep Chatterjee / Elizabeth J Fay / Stefan Knapp / Matthew D Daugherty / Samara L Reck-Peterson / Andres E Leschziner /
Abstract: Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, ...Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinson's disease while LRRK1 is linked to bone diseases. Furthermore, Parkinson's disease-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. Here, to understand these differences, we solved cryo-EM structures of LRRK1 in its monomeric and dimeric forms. Both differ from the corresponding LRRK2 structures. Unlike LRRK2, which is sterically autoinhibited as a monomer, LRRK1 is sterically autoinhibited in a dimer-dependent manner. LRRK1 has an additional level of autoinhibition that prevents activation of the kinase and is absent in LRRK2. Finally, we place the structural signatures of LRRK1 and LRRK2 in the context of the evolution of the LRRK family of proteins.
History
DepositionAug 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release
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Revision 1.1Nov 1, 2023Group: Database references / Category: citation / citation_author
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Revision 1.3May 28, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leucine-rich repeat serine/threonine-protein kinase 1
B: Leucine-rich repeat serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)452,3654
Polymers451,4782
Non-polymers8862
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 225739.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK1, KIAA1790 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q38SD2, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
Has ligand of interestN
Has protein modificationN

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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: Full length LRRK1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2124 nm / Nominal defocus min: 1263 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 58913 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00428342
ELECTRON MICROSCOPYf_angle_d0.70938448
ELECTRON MICROSCOPYf_dihedral_angle_d5.0493792
ELECTRON MICROSCOPYf_chiral_restr0.0444344
ELECTRON MICROSCOPYf_plane_restr0.014926

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