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- EMDB-27813: Structure of monomeric LRRK1 -

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Basic information

Entry
Database: EMDB / ID: EMD-27813
TitleStructure of monomeric LRRK1
Map dataSharpened map for LRRK1 monomer
Sample
  • Complex: LRRK1 20-2015
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 1
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
Keywordsmonomer / TRANSFERASE
Function / homology
Function and homology information


osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / histone H2AS1 kinase activity / non-specific serine/threonine protein kinase / intracellular signal transduction / protein serine/threonine kinase activity / protein serine kinase activity ...osteoclast development / positive regulation of intracellular signal transduction / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / histone H2AS1 kinase activity / non-specific serine/threonine protein kinase / intracellular signal transduction / protein serine/threonine kinase activity / protein serine kinase activity / protein phosphorylation / GTP binding / mitochondrion / ATP binding / identical protein binding / metal ion binding / plasma membrane / 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 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, 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
Leucine-rich repeat serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsReimer JM / Mathea S / Chatterjee D / 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
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_27813.png

Downloads & links

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Map

FileDownload / File: emd_27813.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map for LRRK1 monomer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 288 pix.
= 334.08 Å		1.16 Å/pix.
x 288 pix.
= 334.08 Å		1.16 Å/pix.
x 288 pix.
= 334.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.16 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.239
Minimum - Maximum-1.1104877 - 2.060259
Average (Standard dev.)0.00012840846 (±0.028952852)
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: Half map A for LRRK1 monomer

Fileemd_27813_half_map_1.map
AnnotationHalf map A for LRRK1 monomer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B for LRRK1 monomer

Fileemd_27813_half_map_2.map
AnnotationHalf map B for LRRK1 monomer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : LRRK1 20-2015

EntireName: LRRK1 20-2015
Components
  • Complex: LRRK1 20-2015
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 1
  • Ligand: GUANOSINE-5'-DIPHOSPHATE

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Supramolecule #1: LRRK1 20-2015

SupramoleculeName: LRRK1 20-2015 / 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: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 223.512703 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SAVCPERAME TLNGAGDTGG KPSTRGGDPA ARSRRTEGIR AAYRRGDRGG ARDLLEEACD QCASQLEKGQ LLSIPAAYGD LEMVRYLLS KRLVELPTEP TDDNPAVVAA YFGHTAVVQE LLESLPGPCS PQRLLNWMLA LACQRGHLGV VKLLVLTHGA D PESYAVRK ...String:
SAVCPERAME TLNGAGDTGG KPSTRGGDPA ARSRRTEGIR AAYRRGDRGG ARDLLEEACD QCASQLEKGQ LLSIPAAYGD LEMVRYLLS KRLVELPTEP TDDNPAVVAA YFGHTAVVQE LLESLPGPCS PQRLLNWMLA LACQRGHLGV VKLLVLTHGA D PESYAVRK NEFPVIVRLP LYAAIKSGNE DIAIFLLRHG AYFCSYILLD SPDPSKHLLR KYFIEASPLP SSYPGKTALR VK WSHLRLP WVDLDWLIDI SCQITELDLS ANCLATLPSV IPWGLINLRK LNLSDNHLGE LPGVQSSDEI ICSRLLEIDI SSN KLSHLP PGFLHLSKLQ KLTASKNCLE KLFEEENATN WIGLRKLQEL DISDNKLTEL PALFLHSFKS LNSLNVSRNN LKVF PDPWA CPLKCCKASR NALECLPDKM AVFWKNHLKD VDFSENALKE VPLGLFQLDA LMFLRLQGNQ LAALPPQEKW TCRQL KTLD LSRNQLGKNE DGLKTKRIAF FTTRGRQRSG TEAASVLEFP AFLSESLEVL CLNDNHLDTV PPSVCLLKSL SELYLG NNP GLRELPPELG QLGNLWQLDT EDLTISNVPA EIQKEGPKAM LSYLRAQLRK AEKCKLMKMI IVGPPRQGKS TLLEILQ TG RAPQVVHGEA TIRTTKWELQ RPAGSRAKVE SVEFNVWDIG GPASMATVNQ CFFTDKALYV VVWNLALGEE AVANLQFW L LNIEAKAPNA VVLVVGTHLD LIEAKFRVER IATLRAYVLA LCRSPSGSRA TGFPDITFKH LHEISCKSLE GQEGLRQLI FHVTCSMKDV GSTIGCQRLA GRLIPRSYLS LQEAVLAEQQ RRSRDDDVQY LTDRQLEQLV EQTPDNDIKD YEDLQSAISF LIETGTLLH FPDTSHGLRN LYFLDPIWLS ECLQRIFNIK GSRSVAKNGV IRAEDLRMLL VGTGFTQQTE EQYFQFLAKF E IALPVAND SYLLPHLLPS KPGLDTHGMR HPTANTIQRV FKMSFVPVGF WQRFIARMLI SLAEMDLQLF ENKKNTKSRN RK VTIYSFT GNQRNRCSTF RVKRNQTIYW QEGLLVTFDG GYLSVESSDV NWKKKKSGGM KIVCQSEVRD FSAMAFITDH VNS LIDQWF PALTATESDG TPLMEQYVPC PVCETAWAQH TDPSEKSEDV QYFDMEDCVL TAIERDFISC PRHPDLPVPL QELV PELFM TDFPARLFLE NSKLEHSEDE GSVLGQGGSG TVIYRARYQG QPVAVKRFHI KKFKNFANVP ADTMLRHLRA TDAMK NFSE FRQEASMLHA LQHPCIVALI GISIHPLCFA LELAPLSSLN TVLSENARDS SFIPLGHMLT QKIAYQIASG LAYLHK KNI IFCDLKSDNI LVWSLDVKEH INIKLSDYGI SRQSFHEGAL GVEGTPGYQA PEIRPRIVYD EKVDMFSYGM VLYELLS GQ RPALGHHQLQ IAKKLSKGIR PVLGQPEEVQ FRRLQALMME CWDTKPEKRP LALSVVSQMK DPTFATFMYE LCCGKQTA F FSSQGQEYTV VFWDGKEESR NYTVVNTEKG LMEVQRMCCP GMKVSCQLQV QRSLWTATED QKIYIYTLKG MCPLNTPQQ ALDTPAVVTC FLAVPVIKKN SYLVLAGLAD GLVAVFPVVR GTPKDSCSYL CSHTANRSKF SIADEDARQN PYPVKAMEVV NSGSEVWYS NGPGLLVIDC ASLEICRRLE PYMAPSMVTS VVCSSEGRGE EVVWCLDDKA NSLVMYHSTT YQLCARYFCG V PSPLRDMF PVRPLDTEPP AASHTANPKV PEGDSIADVS IMYSEELGTQ ILIHQESLTD YCSMSSYSSS PPRQAARSPS SL PSSPASS SSVPFSTDCE DSDMLHTPGA ASDRSEHDLT PMDGETFSQH LQAVKILAVR DLIWVPRRGG DVIVIGLEKD SGA QRGRVI AVLKARELTP HGVLVDAAVV AKDTVVCTFE NENTEWCLAV WRGWGAREFD IFYQSYEELG RLEACTRKRR

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: 1 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

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

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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
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 51.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.124 µm / Nominal defocus min: 1.2630000000000001 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 69361
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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