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- EMDB-27815: Local refinement of LRRK1 around the ROC-COR-kinase domains -

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Basic information

Entry
Database: EMDB / ID: EMD-27815
TitleLocal refinement of LRRK1 around the ROC-COR-kinase domains
Map dataLocal refinement around ROC-COR-kinase domains of LRRK1
Sample
  • Complex: Monomeric structure of LRRK1
    • Protein or peptide: Leucine-rich repeat kinase 1
Keywordsmonomer / TRANSFERASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsReimer JM / Mathea S / Knapp S / 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 United States
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_27815.png

Downloads & links

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Map

FileDownload / File: emd_27815.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal refinement around ROC-COR-kinase domains of LRRK1
Voxel sizeX=Y=Z: 1.16 Å
Density
Contour LevelBy AUTHOR: 0.278
Minimum - Maximum-1.298695 - 2.1300676
Average (Standard dev.)0.00012591165 (±0.03191049)
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: Local refinement around ROC-COR-kinase domains of LRRK1, Half map A

Fileemd_27815_half_map_1.map
AnnotationLocal refinement around ROC-COR-kinase domains of LRRK1, Half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Local refinement around ROC-COR-kinase domains of LRRK1, Half map B

Fileemd_27815_half_map_2.map
AnnotationLocal refinement around ROC-COR-kinase domains of LRRK1, Half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Monomeric structure of LRRK1

EntireName: Monomeric structure of LRRK1
Components
  • Complex: Monomeric structure of LRRK1
    • Protein or peptide: Leucine-rich repeat kinase 1

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Supramolecule #1: Monomeric structure of LRRK1

SupramoleculeName: Monomeric structure of LRRK1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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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: SAVCPERAME TLNGAGDTGG KPSTRGGDPA ARSRRTEGIR AAYRRGDRGG ARDLLEEACD QCASQLEKGQ LLSIPAAYGD LEMVRYLLSK RLVELPTEPT DDNPAVVAAY FGHTAVVQEL LESLPGPCSP QRLLNWMLAL ACQRGHLGVV KLLVLTHGAD PESYAVRKNE ...String:
SAVCPERAME TLNGAGDTGG KPSTRGGDPA ARSRRTEGIR AAYRRGDRGG ARDLLEEACD QCASQLEKGQ LLSIPAAYGD LEMVRYLLSK RLVELPTEPT DDNPAVVAAY FGHTAVVQEL LESLPGPCSP QRLLNWMLAL ACQRGHLGVV KLLVLTHGAD PESYAVRKNE FPVIVRLPLY AAIKSGNEDI AIFLLRHGAY FCSYILLDSP DPSKHLLRKY FIEASPLPSS YPGKTALRVK WSHLRLPWVD LDWLIDISCQ ITELDLSANC LATLPSVIPW GLINLRKLNL SDNHLGELPG VQSSDEIICS RLLEIDISSN KLSHLPPGFL HLSKLQKLTA SKNCLEKLFE EENATNWIGL RKLQELDISD NKLTELPALF LHSFKSLNSL NVSRNNLKVF PDPWACPLKC CKASRNALEC LPDKMAVFWK NHLKDVDFSE NALKEVPLGL FQLDALMFLR LQGNQLAALP PQEKWTCRQL KTLDLSRNQL GKNEDGLKTK RIAFFTTRGR QRSGTEAASV LEFPAFLSES LEVLCLNDNH LDTVPPSVCL LKSLSELYLG NNPGLRELPP ELGQLGNLWQ LDTEDLTISN VPAEIQKEGP KAMLSYLRAQ LRKAEKCKLM KMIIVGPPRQ GKSTLLEILQ TGRAPQVVHG EATIRTTKWE LQRPAGSRAK VESVEFNVWD IGGPASMATV NQCFFTDKAL YVVVWNLALG EEAVANLQFW LLNIEAKAPN AVVLVVGTHL DLIEAKFRVE RIATLRAYVL ALCRSPSGSR ATGFPDITFK HLHEISCKSL EGQEGLRQLI FHVTCSMKDV GSTIGCQRLA GRLIPRSYLS LQEAVLAEQQ RRSRDDDVQY LTDRQLEQLV EQTPDNDIKD YEDLQSAISF LIETGTLLHF PDTSHGLRNL YFLDPIWLSE CLQRIFNIKG SRSVAKNGVI RAEDLRMLLV GTGFTQQTEE QYFQFLAKFE IALPVANDSY LLPHLLPSKP GLDTHGMRHP TANTIQRVFK MSFVPVGFWQ RFIARMLISL AEMDLQLFEN KKNTKSRNRK VTIYSFTGNQ RNRCSTFRVK RNQTIYWQEG LLVTFDGGYL SVESSDVNWK KKKSGGMKIV CQSEVRDFSA MAFITDHVNS LIDQWFPALT ATESDGTPLM EQYVPCPVCE TAWAQHTDPS EKSEDVQYFD MEDCVLTAIE RDFISCPRHP DLPVPLQELV PELFMTDFPA RLFLENSKLE HSEDEGSVLG QGGSGTVIYR ARYQGQPVAV KRFHIKKFKN FANVPADTML RHLRATDAMK NFSEFRQEAS MLHALQHPCI VALIGISIHP LCFALELAPL SSLNTVLSEN ARDSSFIPLG HMLTQKIAYQ IASGLAYLHK KNIIFCDLKS DNILVWSLDV KEHINIKLSD YGISRQSFHE GALGVEGTPG YQAPEIRPRI VYDEKVDMFS YGMVLYELLS GQRPALGHHQ LQIAKKLSKG IRPVLGQPEE VQFRRLQALM MECWDTKPEK RPLALSVVSQ MKDPTFATFM YELCCGKQTA FFSSQGQEYT VVFWDGKEES RNYTVVNTEK GLMEVQRMCC PGMKVSCQLQ VQRSLWTATE DQKIYIYTLK GMCPLNTPQQ ALDTPAVVTC FLAVPVIKKN SYLVLAGLAD GLVAVFPVVR GTPKDSCSYL CSHTANRSKF SIADEDARQN PYPVKAMEVV NSGSEVWYSN GPGLLVIDCA SLEICRRLEP YMAPSMVTSV VCSSEGRGEE VVWCLDDKAN SLVMYHSTTY QLCARYFCGV PSPLRDMFPV RPLDTEPPAA SHTANPKVPE GDSIADVSIM YSEELGTQIL IHQESLTDYC SMSSYSSSPP RQAARSPSSL PSSPASSSSV PFSTDCEDSD MLHTPGAASD RSEHDLTPMD GETFSQHLQA VKILAVRDLI WVPRRGGDVI VIGLEKDSGA QRGRVIAVLK ARELTPHGVL VDAAVVAKDT VVCTFENENT EWCLAVWRGW GAREFDIFYQ SYEELGRLEA CTRKRR

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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
Details: 50 mM HEPES pH 7.4, 150 mM NaCl, 5% glycerol, 0.5 mM TCEP, 20 uM GDP
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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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: 51.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: AlphaFold Q38SD2-F1-model-V2
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 69361
FSC plot (resolution estimation)

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