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- EMDB-28952: Cryo-EM map of the LRRK1 dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-28952
TitleCryo-EM map of the LRRK1 dimer
Map data
Sample
  • Complex: Leucine-rich repeat kinase 1
    • Protein or peptide: Leucine-rich repeat kinase 1
Keywordskinase / LRRK / multi-domain protein / GTPase / 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: 6.38 Å
AuthorsMetcalfe RD / Martinez Fiesco JA / Zhang P
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)ZIA BC 011744 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structure and regulation of full-length human leucine-rich repeat kinase 1.
Authors: Riley D Metcalfe / Juliana A Martinez Fiesco / Luis Bonet-Ponce / Jillian H Kluss / Mark R Cookson / Ping Zhang /
Abstract: The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human ...The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human disease. Structures of LRRK2 have recently been determined, but the structure and molecular mechanisms regulating the activity of the LRRK1 as well as differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces that control kinase activity as we validate experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2. Overall, our results provide structural insights into the activation of the human LRRKs, which advance our understanding of their physiological and pathological roles.
History
DepositionNov 25, 2022-
Header (metadata) releaseAug 16, 2023-
Map releaseAug 16, 2023-
UpdateAug 16, 2023-
Current statusAug 16, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28952.png

Downloads & links

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Map

FileDownload / File: emd_28952.map.gz / Format: CCP4 / Size: 307.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.81 Å
Density
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.12924501 - 0.20278655
Average (Standard dev.)-0.00012587577 (±0.008341554)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions432432432
Spacing432432432
CellA=B=C: 349.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_28952_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram (log scale)

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Additional map: #1

Fileemd_28952_additional_1.map
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Half map: #1

Fileemd_28952_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_28952_half_map_2.map
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Sample components

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Entire : Leucine-rich repeat kinase 1

EntireName: Leucine-rich repeat kinase 1
Components
  • Complex: Leucine-rich repeat kinase 1
    • Protein or peptide: Leucine-rich repeat kinase 1

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Supramolecule #1: Leucine-rich repeat kinase 1

SupramoleculeName: Leucine-rich repeat kinase 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230 KDa

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Macromolecule #1: Leucine-rich repeat kinase 1

MacromoleculeName: Leucine-rich repeat kinase 1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDYKDHDGDY KDHDIDYKDD DDKLGLEVLF QGPMAGMSQR PPSMYWCVGP EESAVCPERA METLNGAGDT GGKPSTRGGD PAARSRRTEG IRAAYRRGDR GGARDLLEEA CDQCASQLEK GQLLSIPAAY GDLEMVRYLL SKRLVELPTE PTDDNPAVVA AYFGHTAVVQ ...String:
MDYKDHDGDY KDHDIDYKDD DDKLGLEVLF QGPMAGMSQR PPSMYWCVGP EESAVCPERA METLNGAGDT GGKPSTRGGD PAARSRRTEG IRAAYRRGDR GGARDLLEEA CDQCASQLEK GQLLSIPAAY GDLEMVRYLL SKRLVELPTE PTDDNPAVVA AYFGHTAVVQ ELLESLPGPC SPQRLLNWML ALACQRGHLG VVKLLVLTHG ADPESYAVRK NEFPVIVRLP LYAAIKSGNE DIAIFLLRHG AYFCSYILLD SPDPSKHLLR KYFIEASPLP SSYPGKTALR VKWSHLRLPW VDLDWLIDIS CQITELDLSA NCLATLPSVI PWGLINLRKL NLSDNHLGEL PGVQSSDEII CSRLLEIDIS SNKLSHLPPG FLHLSKLQKL TASKNCLEKL FEEENATNWI GLRKLQELDI SDNKLTELPA LFLHSFKSLN SLNVSRNNLK VFPDPWACPL KCCKASRNAL ECLPDKMAVF WKNHLKDVDF SENALKEVPL GLFQLDALMF LRLQGNQLAA LPPQEKWTCR QLKTLDLSRN QLGKNEDGLK TKRIAFFTTR GRQRSGTEAA SVLEFPAFLS ESLEVLCLND NHLDTVPPSV CLLKSLSELY LGNNPGLREL PPELGQLGNL WQLDTEDLTI SNVPAEIQKE GPKAMLSYLR AQLRKAEKCK LMKMIIVGPP RQGKSTLLEI LQTGRAPQVV HGEATIRTTK WELQRPAGSR AKVESVEFNV WDIGGPASMA TVNQCFFTDK ALYVVVWNLA LGEEAVANLQ FWLLNIEAKA PNAVVLVVGT HLDLIEAKFR VERIATLRAY VLALCRSPSG SRATGFPDIT FKHLHEISCK SLEGQEGLRQ LIFHVTCSMK DVGSTIGCQR LAGRLIPRSY LSLQEAVLAE QQRRSRDDDV QYLTDRQLEQ LVEQTPDNDI KDYEDLQSAI SFLIETGTLL HFPDTSHGLR NLYFLDPIWL SECLQRIFNI KGSRSVAKNG VIRAEDLRML LVGTGFTQQT EEQYFQFLAK FEIALPVAND SYLLPHLLPS KPGLDTHGMR HPTANTIQRV FKMSFVPVGF WQRFIARMLI SLAEMDLQLF ENKKNTKSRN RKVTIYSFTG NQRNRCSTFR VKRNQTIYWQ EGLLVTFDGG YLSVESSDVN WKKKKSGGMK IVCQSEVRDF SAMAFITDHV NSLIDQWFPA LTATESDGTP LMEQYVPCPV CETAWAQHTD PSEKSEDVQY FDMEDCVLTA IERDFISCPR HPDLPVPLQE LVPELFMTDF PARLFLENSK LEHSEDEGSV LGQGGSGTVI YRARYQGQPV AVKRFHIKKF KNFANVPADT MLRHLRATDA MKNFSEFRQE ASMLHALQHP CIVALIGISI HPLCFALELA PLSSLNTVLS ENARDSSFIP LGHMLTQKIA YQIASGLAYL HKKNIIFCDL KSDNILVWSL DVKEHINIKL SDYGISRQSF HEGALGVEGT PGYQAPEIRP RIVYDEKVDM FSYGMVLYEL LSGQRPALGH HQLQIAKKLS KGIRPVLGQP EEVQFRRLQA LMMECWDTKP EKRPLALSVV SQMKDPTFAT FMYELCCGKQ TAFFSSQGQE YTVVFWDGKE ESRNYTVVNT EKGLMEVQRM CCPGMKVSCQ LQVQRSLWTA TEDQKIYIYT LKGMCPLNTP QQALDTPAVV TCFLAVPVIK KNSYLVLAGL ADGLVAVFPV VRGTPKDSCS YLCSHTANRS KFSIADEDAR QNPYPVKAME VVNSGSEVWY SNGPGLLVID CASLEICRRL EPYMAPSMVT SVVCSSEGRG EEVVWCLDDK ANSLVMYHST TYQLCARYFC GVPSPLRDMF PVRPLDTEPP AASHTANPKV PEGDSIADVS IMYSEELGTQ ILIHQESLTD YCSMSSYSSS PPRQAARSPS SLPSSPASSS SVPFSTDCED SDMLHTPGAA SDRSEHDLTP MDGETFSQHL QAVKILAVRD LIWVPRRGGD VIVIGLEKDS GAQRGRVIAV LKARELTPHG VLVDAAVVAK DTVVCTFENE NTEWCLAVWR GWGAREFDIF YQSYEELGRL EACTRKRR

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

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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

Concentration0.2 mg/mL
BufferpH: 8.3
VitrificationCryogen name: ETHANE / Instrument: LEICA EM GP
DetailsPurified LRRK1

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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: 2.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 7 / Number real images: 18074 / Average exposure time: 2.5 sec. / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3553719
Details: Particles picked using a Topaz model trained on an initial LRRK1 dataset.
Startup modelType of model: NONE / Details: Ab-initio model generated using Cryosparc.
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.38 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 55178
FSC plot (resolution estimation)

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