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- EMDB-29341: Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state -

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Entry
Database: EMDB / ID: EMD-29341
TitleCryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state
Map data
Sample
  • Complex: Rab29-LRRK2
    • Protein or peptide: Ras-related protein Rab-7L1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
KeywordsCryo-EM / Parkinson's disease / Kinase / LRRK2 / Rab GTPases / Activation / HYDROLASE
Function / homology
Function and homology information


protein localization to ciliary membrane / caveola neck / negative regulation of protein processing involved in protein targeting to mitochondrion / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / Wnt signalosome assembly / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / GTP-dependent protein kinase activity ...protein localization to ciliary membrane / caveola neck / negative regulation of protein processing involved in protein targeting to mitochondrion / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / Wnt signalosome assembly / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / GTP-dependent protein kinase activity / regulation of SNARE complex assembly / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / protein localization to endoplasmic reticulum exit site / peroxidase inhibitor activity / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / positive regulation of dopamine receptor signaling pathway / amphisome / regulation of synaptic vesicle transport / regulation of lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / co-receptor binding / negative regulation of GTPase activity / positive regulation of intracellular protein transport / host-mediated perturbation of viral process / regulation of dopamine receptor signaling pathway / regulation of neuron maturation / positive regulation of microglial cell activation / regulation of retrograde transport, endosome to Golgi / positive regulation of synaptic vesicle endocytosis / cytoplasmic side of mitochondrial outer membrane / negative regulation of excitatory postsynaptic potential / negative regulation of autophagosome assembly / JUN kinase kinase kinase activity / olfactory bulb development / RAB geranylgeranylation / neuron projection arborization / melanosome organization / striatum development / multivesicular body, internal vesicle / regulation of dendritic spine morphogenesis / mitochondrion localization / cis-Golgi network / protein localization to mitochondrion / cellular response to dopamine / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / vacuole / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / Wnt signalosome / negative regulation of protein processing / positive regulation of programmed cell death / retrograde transport, endosome to Golgi / protein localization to membrane / GTP metabolic process / regulation of canonical Wnt signaling pathway / cellular detoxification / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / lysosome organization / Golgi-associated vesicle / clathrin binding / PTK6 promotes HIF1A stabilization / negative regulation of macroautophagy / protein kinase A binding / neuromuscular junction development / regulation of cAMP/PKA signal transduction / regulation of mitochondrial fission / regulation of locomotion / intracellular vesicle / regulation of synaptic vesicle exocytosis / microvillus / Golgi organization / intracellular distribution of mitochondria / positive regulation of T cell receptor signaling pathway / exploration behavior / endoplasmic reticulum exit site / autolysosome / dynein complex binding / positive regulation of receptor recycling / locomotory exploration behavior / negative regulation of Notch signaling pathway / kinesin binding / MAP kinase kinase kinase activity / regulation of synaptic vesicle endocytosis / canonical Wnt signaling pathway / regulation of synaptic transmission, glutamatergic / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / presynaptic cytosol / synapse assembly / Rho protein signal transduction / neuron projection morphogenesis / phagocytic vesicle / cellular response to manganese ion / JNK cascade / endomembrane system / positive regulation of autophagy / dendrite cytoplasm
Similarity search - Function
Ras-related protein Rab29/Rab38/Rab32 / : / : / : / LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc, COR-B domain / C-terminal of Roc (COR) domain ...Ras-related protein Rab29/Rab38/Rab32 / : / : / : / LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc, COR-B domain / 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 / Small GTPase Rab domain profile. / Leucine-rich repeats, bacterial type / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Leucine-rich repeat profile. / Leucine-rich repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Leucine-rich repeat domain superfamily / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Small GTP-binding protein domain / Armadillo-type fold / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / WD40-repeat-containing domain superfamily / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Ras-related protein Rab-7L1 / Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.88 Å
AuthorsZhu H / Sun J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R00HL143037 United States
Citation
Journal: Science / Year: 2023
Title: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.
Authors: Hanwen Zhu / Francesca Tonelli / Martin Turk / Alan Prescott / Dario R Alessi / Ji Sun /
Abstract: Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles ...Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment.
#1: Journal: bioRxiv / Year: 2022
Title: Structural basis of human LRRK2 membrane recruitment and activation
Authors: Zhu H / Tonelli F / Alessi D / Sun J
History
DepositionDec 29, 2022-
Header (metadata) releaseJan 3, 2024-
Map releaseJan 3, 2024-
UpdateJan 3, 2024-
Current statusJan 3, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29341.png

Downloads & links

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Map

FileDownload / File: emd_29341.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 480 pix.
= 508.8 Å		1.06 Å/pix.
x 480 pix.
= 508.8 Å		1.06 Å/pix.
x 480 pix.
= 508.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-1.7427796 - 2.795068
Average (Standard dev.)0.001138748 (±0.041371215)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 508.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_29341_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_29341_half_map_2.map
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Sample components

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Entire : Rab29-LRRK2

EntireName: Rab29-LRRK2
Components
  • Complex: Rab29-LRRK2
    • Protein or peptide: Ras-related protein Rab-7L1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: Rab29-LRRK2

SupramoleculeName: Rab29-LRRK2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Ras-related protein Rab-7L1

MacromoleculeName: Ras-related protein Rab-7L1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.239076 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGSRDHLFKV LVVGDAAVGK TSLVQRYSQD SFSKHYKSTV GVDFALKVLQ WSDYEIVRLQ LWDIAGLERF AAMTRLYYRD ASACVIMFD VTNATTFSNS QRWKQDLDSK LTLPNGEPVP CLLLANKCDL SPWAVSRDQI DRFSKENGFT GWTETSVKEN K NINEAMRV LIEKMMRNS

UniProtKB: Ras-related protein Rab-7L1

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Macromolecule #2: Leucine-rich repeat serine/threonine-protein kinase 2

MacromoleculeName: Leucine-rich repeat serine/threonine-protein kinase 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 286.427656 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSEH ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLI EVCPGTMQSL MGPQDVGNDW EVLGVHQLIL KMLTVHNASV NLSVIGLKTL DLLLTSGKIT LLILDEESDI F MLIFDAMH ...String:
MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSEH ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLI EVCPGTMQSL MGPQDVGNDW EVLGVHQLIL KMLTVHNASV NLSVIGLKTL DLLLTSGKIT LLILDEESDI F MLIFDAMH SFPANDEVQK LGCKALHVLF ERVSEEQLTE FVENKDYMIL LSALTNFKDE EEIVLHVLHC LHSLAIPCNN VE VLMSGNV RCYNIVVEAM KAFPMSERIQ EVSCCLLHRL TLGNFFNILV LNEVHEFVVK AVQQYPENAA LQISALSCLA LLT ETIFLN QDLEEKNENQ ENDDEGEEDK LFWLEACYKA LTWHRKNKHV QEAACWALNN LLMYQNSLHE KIGDEDGHFP AHRE VMLSM LMHSSSKEVF QASANALSTL LEQNVNFRKI LLSKGIHLNV LELMQKHIHS PEVAESGCKM LNHLFEGSNT SLDIM AAVV PKILTVMKRH ETSLPVQLEA LRAILHFIVP GMPEESREDT EFHHKLNMVK KQCFKNDIHK LVLAALNRFI GNPGIQ KCG LKVISSIVHF PDALEMLSLE GAMDSVLHTL QMYPDDQEIQ CLGLSLIGYL ITKKNVFIGT GHLLAKILVS SLYRFKD VA EIQTKGFQTI LAILKLSASF SKLLVHHSFD LVIFHQMSSN IMEQKDQQFL NLCCKCFAKV AMDDYLKNVM LERACDQN N SIMVECLLLL GADANQAKEG SSLICQVCEK ESSPKLVELL LNSGSREQDV RKALTISIGK GDSQIISLLL RRLALDVAN NSICLGGFCI GKVEPSWLGP LFPDKTSNLR KQTNIASTLA RMVIRYQMKS AVEEGTASGS DGNFSEDVLS KFDEWTFIPD SSMDSVFAQ SDDLDSEGSE GSFLVKKKSN SISVGEFYRD AVLQRCSPNL QRHSNSLGPI FDHEDLLKRK RKILSSDDSL R SSKLQSHM RHSDSISSLA SEREYITSLD LSANELRDID ALSQKCCISV HLEHLEKLEL HQNALTSFPQ QLCETLKSLT HL DLHSNKF TSFPSYLLKM SCIANLDVSR NDIGPSVVLD PTVKCPTLKQ FNLSYNQLSF VPENLTDVVE KLEQLILEGN KIS GICSPL RLKELKILNL SKNHISSLSE NFLEACPKVE SFSARMNFLA AMPFLPPSMT ILKLSQNKFS CIPEAILNLP HLRS LDMSS NDIQYLPGPA HWKSLNLREL LFSHNQISIL DLSEKAYLWS RVEKLHLSHN KLKEIPPEIG CLENLTSLDV SYNLE LRSF PNEMGKLSKI WDLPLDELHL NFDFKHIGCK AKDIIRFLQQ RLKKAVPYNR MKLMIVGNTG SGKTTLLQQL MKTKKS DLG MQSATVGIDV KDWPIQIRDK RKRDLVLNVW DFAGREEFYS THPHFMTQRA LYLAVYDLSK GQAEVDAMKP WLFNIKA RA SSSPVILVGT HLDVSDEKQR KACMSKITKE LLNKRGFPAI RDYHFVNATE ESDALAKLRK TIINESLNFK IRDQLVVG Q LIPDCYVELE KIILSERKNV PIEFPVIDRK RLLQLVRENQ LQLDENELPH AVHFLNESGV LLHFQDPALQ LSDLYFVEP KWLCKIMAQI LTVKVEGCPK HPKGIISRRD VEKFLSKKRK FPKNYMTQYF KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI ELPHCENSE IIIRLYEMPY FPMGFWSRLI NRLLEISPYM LSGRERALRP NRMYWRQGIY LNWSPEAYCL VGSEVLDNHP E SFLKITVP SCRKGCILLG QVVDHIDSLM EEWFPGLLEI DICGEGETLL KKWALYSFND GEEHQKILLD DLMKKAEEGD LL VNPDQPR LTIPISQIAP DLILADLPRN IMLNNDELEF EQAPEFLLGD GSFGSVYRAA YEGEEVAVKI FNKHTSLRLL RQE LVVLCH LHHPSLISLL AAGIRPRMLV MELASKGSLD RLLQQDKASL TRTLQHRIAL HVADGLRYLH SAMIIYRDLK PHNV LLFTL YPNAAIIAKI ADYGIAQYCC RMGIKTSEGT PGFRAPEVAR GNVIYNQQAD VYSFGLLLYD ILTTGGRIVE GLKFP NEFD ELEIQGKLPD PVKEYGCAPW PMVEKLIKQC LKENPQERPT SAQVFDILNS AELVCLTRRI LLPKNVIVEC MVATHH NSR NASIWLGCGH TDRGQLSFLD LNTEGYTSEE VADSRILCLA LVHLPVEKES WIVSGTQSGT LLVINTEDGK KRHTLEK MT DSVTCLYCNS FSKQSKQKNF LLVGTADGKL AIFEDKTVKL KGAAPLKILN IGNVSTPLMC LSESTNSTER NVMWGGCG T KIFSFSNDFT IQKLIETRTS QLFSYAAFSD SNIITVVVDT ALYIAKQNSP VVEVWDKKTE KLCGLIDCVH FLREVTVKE NKESKHKMSY SGRVKTLCLQ KNTALWIGTG GGHILLLDLS TRRLIRVIYN FCNSVRVMMT AQLGSLKNVM LVLGYNRKNT EGTQKQKEI QSCLTVWDIN LPHEVQNLEK HIEVRKELAE KMRRTSVE

UniProtKB: Leucine-rich repeat serine/threonine-protein kinase 2

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Macromolecule #3: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

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

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Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, 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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.88 Å / Resolution method: OTHER / Software - Name: cryoSPARC / Number images used: 96502
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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