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- EMDB-27817: Structure of dimeric LRRK1 -

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Basic information

Entry
Database: EMDB / ID: EMD-27817
TitleStructure of dimeric LRRK1
Map data
Sample
  • Complex: Full length LRRK1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 1
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
Keywordsdimer / TRANSFERASE
Function / homology
Function and homology information


negative regulation of peptidyl-tyrosine phosphorylation / osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of canonical Wnt signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity ...negative regulation of peptidyl-tyrosine phosphorylation / osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of canonical Wnt signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / GTP binding / mitochondrion / ATP binding / identical protein binding / metal ion binding / cytosol
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 / Leucine-rich repeat domain superfamily / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / 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
Leucine-rich repeat serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsReimer JM / Lin YX / Leschziner AE
Funding support United States, 4 items
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, 2022-
Header (metadata) releaseAug 30, 2023-
Map releaseAug 30, 2023-
UpdateNov 29, 2023-
Current statusNov 29, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27817.png

Downloads & links

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Map

FileDownload / File: emd_27817.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.16 Å
Density
Contour LevelBy AUTHOR: 0.134
Minimum - Maximum-0.37228662 - 0.6986543
Average (Standard dev.)0.0010045033 (±0.023127394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 334.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_27817_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_27817_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Full length LRRK1

EntireName: Full length LRRK1
Components
  • Complex: Full length LRRK1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 1
  • Ligand: GUANOSINE-5'-DIPHOSPHATE

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Supramolecule #1: Full length LRRK1

SupramoleculeName: Full length LRRK1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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

MacromoleculeName: Leucine-rich repeat serine/threonine-protein kinase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 225.739219 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SMAGMSQRPP SMYWCVGPEE SAVCPERAME TLNGAGDTGG KPSTRGGDPA ARSRRTEGIR AAYRRGDRGG ARDLLEEACD QCASQLEKG QLLSIPAAYG DLEMVRYLLS KRLVELPTEP TDDNPAVVAA YFGHTAVVQE LLESLPGPCS PQRLLNWMLA L ACQRGHLG ...String:
SMAGMSQRPP SMYWCVGPEE SAVCPERAME TLNGAGDTGG KPSTRGGDPA ARSRRTEGIR AAYRRGDRGG ARDLLEEACD QCASQLEKG QLLSIPAAYG DLEMVRYLLS KRLVELPTEP TDDNPAVVAA YFGHTAVVQE LLESLPGPCS PQRLLNWMLA L ACQRGHLG VVKLLVLTHG ADPESYAVRK NEFPVIVRLP LYAAIKSGNE DIAIFLLRHG AYFCSYILLD SPDPSKHLLR KY FIEASPL PSSYPGKTAL RVKWSHLRLP WVDLDWLIDI SCQITELDLS ANCLATLPSV IPWGLINLRK LNLSDNHLGE LPG VQSSDE IICSRLLEID ISSNKLSHLP PGFLHLSKLQ KLTASKNCLE KLFEEENATN WIGLRKLQEL DISDNKLTEL PALF LHSFK SLNSLNVSRN NLKVFPDPWA CPLKCCKASR NALECLPDKM AVFWKNHLKD VDFSENALKE VPLGLFQLDA LMFLR LQGN QLAALPPQEK WTCRQLKTLD LSRNQLGKNE DGLKTKRIAF FTTRGRQRSG TEAASVLEFP AFLSESLEVL CLNDNH LDT VPPSVCLLKS LSELYLGNNP GLRELPPELG QLGNLWQLDT EDLTISNVPA EIQKEGPKAM LSYLRAQLRK AEKCKLM KM IIVGPPRQGK STLLEILQTG RAPQVVHGEA TIRTTKWELQ RPAGSRAKVE SVEFNVWDIG GPASMATVNQ CFFTDKAL Y VVVWNLALGE EAVANLQFWL LNIEAKAPNA VVLVVGTHLD LIEAKFRVER IATLRAYVLA LCRSPSGSRA TGFPDITFK HLHEISCKSL EGQEGLRQLI FHVTCSMKDV GSTIGCQRLA GRLIPRSYLS LQEAVLAEQQ RRSRDDDVQY LTDRQLEQLV EQTPDNDIK DYEDLQSAIS FLIETGTLLH FPDTSHGLRN LYFLDPIWLS ECLQRIFNIK GSRSVAKNGV IRAEDLRMLL V GTGFTQQT EEQYFQFLAK FEIALPVAND SYLLPHLLPS KPGLDTHGMR HPTANTIQRV FKMSFVPVGF WQRFIARMLI SL AEMDLQL FENKKNTKSR NRKVTIYSFT GNQRNRCSTF RVKRNQTIYW QEGLLVTFDG GYLSVESSDV NWKKKKSGGM KIV CQSEVR DFSAMAFITD HVNSLIDQWF PALTATESDG TPLMEQYVPC PVCETAWAQH TDPSEKSEDV QYFDMEDCVL TAIE RDFIS CPRHPDLPVP LQELVPELFM TDFPARLFLE NSKLEHSEDE GSVLGQGGSG TVIYRARYQG QPVAVKRFHI KKFKN FANV PADTMLRHLR ATDAMKNFSE FRQEASMLHA LQHPCIVALI GISIHPLCFA LELAPLSSLN TVLSENARDS SFIPLG HML TQKIAYQIAS GLAYLHKKNI IFCDLKSDNI LVWSLDVKEH INIKLSDYGI SRQSFHEGAL GVEGTPGYQA PEIRPRI VY DEKVDMFSYG MVLYELLSGQ RPALGHHQLQ IAKKLSKGIR PVLGQPEEVQ FRRLQALMME CWDTKPEKRP LALSVVSQ M KDPTFATFMY ELCCGKQTAF FSSQGQEYTV VFWDGKEESR NYTVVNTEKG LMEVQRMCCP GMKVSCQLQV QRSLWTATE DQKIYIYTLK GMCPLNTPQQ ALDTPAVVTC FLAVPVIKKN SYLVLAGLAD GLVAVFPVVR GTPKDSCSYL CSHTANRSKF SIADEDARQ NPYPVKAMEV VNSGSEVWYS NGPGLLVIDC ASLEICRRLE PYMAPSMVTS VVCSSEGRGE EVVWCLDDKA N SLVMYHST TYQLCARYFC GVPSPLRDMF PVRPLDTEPP AASHTANPKV PEGDSIADVS IMYSEELGTQ ILIHQESLTD YC SMSSYSS SPPRQAARSP SSLPSSPASS SSVPFSTDCE DSDMLHTPGA ASDRSEHDLT PMDGETFSQH LQAVKILAVR DLI WVPRRG GDVIVIGLEK DSGAQRGRVI AVLKARELTP HGVLVDAAVV AKDTVVCTFE NENTEWCLAV WRGWGAREFD IFYQ SYEEL GRLEACTRKR R

UniProtKB: Leucine-rich repeat serine/threonine-protein kinase 1

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Macromolecule #2: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.124 µm / Nominal defocus min: 1.2630000000000001 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 55.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 58913

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