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Yorodumi- EMDB-29342: Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 tetramer state -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-29342 | |||||||||
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Title | Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 tetramer state | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Cryo-EM / Parkinson's disease / Kinase / LRRK2 / Rab GTPases / Activation / HYDROLASE | |||||||||
Function / homology | Function and homology information protein localization to ciliary membrane / peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / regulation of branching morphogenesis of a nerve / beta-catenin destruction complex binding / regulation of kidney size / regulation of neuron maturation ...protein localization to ciliary membrane / peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / regulation of branching morphogenesis of a nerve / beta-catenin destruction complex binding / regulation of kidney size / regulation of neuron maturation / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / regulation of synaptic vesicle transport / regulation of lysosomal lumen pH / positive regulation of dopamine receptor signaling pathway / amphisome / regulation of CAMKK-AMPK signaling cascade / cytoplasmic side of mitochondrial outer membrane / regulation of protein kinase A signaling / co-receptor binding / modulation by host of viral process / mitochondrion localization / regulation of retrograde transport, endosome to Golgi / negative regulation of excitatory postsynaptic potential / regulation of dopamine receptor signaling pathway / negative regulation of autophagosome assembly / positive regulation of microglial cell activation / neuron projection arborization / positive regulation of synaptic vesicle endocytosis / JUN kinase kinase kinase activity / RAB geranylgeranylation / olfactory bulb development / positive regulation of intracellular protein transport / regulation of dendritic spine morphogenesis / melanosome organization / striatum development / multivesicular body, internal vesicle / protein localization to mitochondrion / protein localization to membrane / cis-Golgi network / cellular response to dopamine / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / presynaptic cytosol / retrograde transport, endosome to Golgi / positive regulation of programmed cell death / vacuole / Wnt signalosome / cellular detoxification / GTP metabolic process / regulation of canonical Wnt signaling pathway / negative regulation of protein processing / negative regulation of GTPase activity / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / exploration behavior / protein kinase A binding / regulation of locomotion / regulation of synaptic vesicle exocytosis / clathrin binding / PTK6 promotes HIF1A stabilization / Golgi-associated vesicle / negative regulation of macroautophagy / neuromuscular junction development / intracellular vesicle / lysosome organization / dynein complex binding / positive regulation of receptor recycling / positive regulation of T cell receptor signaling pathway / regulation of mitochondrial fission / intracellular distribution of mitochondria / autolysosome / Golgi organization / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / endoplasmic reticulum exit site / kinesin binding / microvillus / Rho protein signal transduction / MAP kinase kinase kinase activity / positive regulation of protein kinase activity / endomembrane system / cellular response to manganese ion / canonical Wnt signaling pathway / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of autophagy / phosphorylation / JNK cascade / regulation of synaptic transmission, glutamatergic / synapse assembly / dendrite cytoplasm / cellular response to starvation / GTPase activator activity / tubulin binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.48 Å | |||||||||
Authors | Zhu H / Sun J | |||||||||
Funding support | United States, 1 items
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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. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_29342.map.gz | 398.6 MB | EMDB map data format | |
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Header (meta data) | emd-29342-v30.xml emd-29342.xml | 21.8 KB 21.8 KB | Display Display | EMDB header |
Images | emd_29342.png | 73.5 KB | ||
Filedesc metadata | emd-29342.cif.gz | 7.2 KB | ||
Others | emd_29342_additional_1.map.gz emd_29342_additional_2.map.gz emd_29342_half_map_1.map.gz emd_29342_half_map_2.map.gz | 398.7 MB 398.2 MB 391 MB 391 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-29342 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-29342 | HTTPS FTP |
-Validation report
Summary document | emd_29342_validation.pdf.gz | 938.1 KB | Display | EMDB validaton report |
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Full document | emd_29342_full_validation.pdf.gz | 937.6 KB | Display | |
Data in XML | emd_29342_validation.xml.gz | 17.9 KB | Display | |
Data in CIF | emd_29342_validation.cif.gz | 21.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29342 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29342 | HTTPS FTP |
-Related structure data
Related structure data | 8fo9MC 8fo2C 8fo8C 8smcC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_29342.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: local refinement map for central LRRK2 copies
File | emd_29342_additional_1.map | ||||||||||||
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Annotation | local refinement map for central LRRK2 copies | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: composite map
File | emd_29342_additional_2.map | ||||||||||||
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Annotation | composite map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_29342_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_29342_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Rab29-LRRK2
Entire | Name: Rab29-LRRK2 |
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Components |
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-Supramolecule #1: Rab29-LRRK2
Supramolecule | Name: Rab29-LRRK2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Leucine-rich repeat serine/threonine-protein kinase 2
Macromolecule | Name: Leucine-rich repeat serine/threonine-protein kinase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 286.427656 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: Ras-related protein Rab-7L1
Macromolecule | Name: Ras-related protein Rab-7L1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 20.239076 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 |
-Macromolecule #3: GUANOSINE-5'-DIPHOSPHATE
Macromolecule | Name: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 4 / Formula: GDP |
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Molecular weight | Theoretical: 443.201 Da |
Chemical component information | ChemComp-GDP: |
-Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE
Macromolecule | Name: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 4 / Formula: ATP |
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Molecular weight | Theoretical: 507.181 Da |
Chemical component information | ChemComp-ATP: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.8 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.48 Å / Resolution method: OTHER / Software - Name: cryoSPARC / Number images used: 40694 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |