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- EMDB-12700: Structure of the C9orf72-SMCR8 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-12700
TitleStructure of the C9orf72-SMCR8 complex
Map dataMap of C9orf72-SMCR8 complex
Sample
  • Complex: C9orf72-SMCR8 complex
    • Protein or peptide: Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72
    • Protein or peptide: Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exchange protein SMCR8,Maltose/maltodextrin-binding periplasmic protein
Function / homology
Function and homology information


Atg1/ULK1 kinase complex / SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMOylation of SUMOylation proteins / SUMO is proteolytically processed / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / late endosome to lysosome transport / SUMOylation of transcription cofactors ...Atg1/ULK1 kinase complex / SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMOylation of SUMOylation proteins / SUMO is proteolytically processed / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / late endosome to lysosome transport / SUMOylation of transcription cofactors / regulation of TORC1 signaling / septin ring / SUMOylation of DNA damage response and repair proteins / SUMOylation of RNA binding proteins / regulation of autophagosome assembly / negative regulation of autophagosome assembly / SUMOylation of DNA replication proteins / regulation of actin filament organization / guanyl-nucleotide exchange factor complex / SUMOylation of chromatin organization proteins / negative regulation of immune response / axon extension / negative regulation of exocytosis / Flemming body / positive regulation of autophagosome maturation / main axon / negative regulation of macroautophagy / detection of maltose stimulus / maltose binding / maltose transport complex / protein kinase inhibitor activity / maltose transport / maltodextrin transmembrane transport / ubiquitin-like protein ligase binding / positive regulation of macroautophagy / protein sumoylation / carbohydrate transmembrane transporter activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / carbohydrate transport / positive regulation of TOR signaling / autophagosome / stress granule assembly / axonal growth cone / ATP-binding cassette (ABC) transporter complex / GTPase activator activity / cell chemotaxis / guanyl-nucleotide exchange factor activity / negative regulation of protein phosphorylation / condensed nuclear chromosome / regulation of autophagy / cell projection / P-body / negative regulation of protein kinase activity / protein tag activity / small GTPase binding / autophagy / positive regulation of GTPase activity / cytoplasmic stress granule / endocytosis / regulation of protein localization / presynapse / outer membrane-bounded periplasmic space / perikaryon / postsynapse / nuclear membrane / lysosome / periplasmic space / endosome / negative regulation of gene expression / intracellular membrane-bounded organelle / dendrite / DNA damage response / chromatin / protein kinase binding / extracellular space / nucleoplasm / membrane / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Guanine nucleotide exchange factor C9orf72 / C9orf72-like protein family / Tripartite DENN C9ORF72-type domain profile. / Folliculin/SMCR8, longin domain / Folliculin/SMCR8, tripartite DENN domain / Vesicle coat protein involved in Golgi to plasma membrane transport / Tripartite DENN FLCN/SMCR8-type domain profile. / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Maltose/Cyclodextrin ABC transporter, substrate-binding protein ...Guanine nucleotide exchange factor C9orf72 / C9orf72-like protein family / Tripartite DENN C9ORF72-type domain profile. / Folliculin/SMCR8, longin domain / Folliculin/SMCR8, tripartite DENN domain / Vesicle coat protein involved in Golgi to plasma membrane transport / Tripartite DENN FLCN/SMCR8-type domain profile. / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Maltose/maltodextrin-binding periplasmic protein / Ubiquitin-like protein SMT3 / Guanine nucleotide exchange protein SMCR8 / Guanine nucleotide exchange factor C9orf72
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli K-12 (bacteria)
Methodsingle particle reconstruction / cryo EM
AuthorsNoerpel J / Cavadini S / Schenk AD / Graff-Meyer A / Chao J / Bhaskar V
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: PLoS Biol / Year: 2021
Title: Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.
Authors: Julia Nörpel / Simone Cavadini / Andreas D Schenk / Alexandra Graff-Meyer / Daniel Hess / Jan Seebacher / Jeffrey A Chao / Varun Bhaskar /
Abstract: A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 repeat expansion in the first intron of the C9orf72 gene. ...A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 repeat expansion in the first intron of the C9orf72 gene. Many underlying mechanisms lead to manifestation of disease that include toxic gain-of-function by repeat G4C2 RNAs, dipeptide repeat proteins, and a reduction of the C9orf72 gene product. The C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy. Here, we report the structure of the C9orf72-SMCR8 complex at 3.8 Å resolution using single-particle cryo-electron microscopy (cryo-EM). The structure reveals 2 distinct dimerization interfaces between C9orf72 and SMCR8 that involves an extensive network of interactions. Homology between C9orf72-SMCR8 and Folliculin-Folliculin Interacting Protein 2 (FLCN-FNIP2), a GTPase activating protein (GAP) complex, enabled identification of a key residue within the active site of SMCR8. Further structural analysis suggested that a coiled-coil region within the uDenn domain of SMCR8 could act as an interaction platform for other coiled-coil proteins, and its deletion reduced the interaction of the C9orf72-SMCR8 complex with FIP200 upon starvation. In summary, this study contributes toward our understanding of the biological function of the C9orf72-SMCR8 complex.
History
DepositionMar 31, 2021-
Header (metadata) releaseJul 21, 2021-
Map releaseJul 21, 2021-
UpdateFeb 2, 2022-
Current statusFeb 2, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.003
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.003
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7o2w
  • Surface level: 0.003
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12700.png

Downloads & links

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Map

FileDownload / File: emd_12700.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap of C9orf72-SMCR8 complex
Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 0.0022 / Movie #1: 0.003
Minimum - Maximum-0.009701821 - 0.015951749
Average (Standard dev.)2.25176e-05 (±0.0003570773)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 240.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.860.860.86
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z240.800240.800240.800
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0100.0160.000

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Supplemental data

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Additional map: Unsharpened map of C9orf72-SMCR8 complex

Fileemd_12700_additional_1.map
AnnotationUnsharpened map of C9orf72-SMCR8 complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map of C9orf72-SMCR8 complex at 4.3 angstrong

Fileemd_12700_additional_2.map
AnnotationUnsharpened map of C9orf72-SMCR8 complex at 4.3 angstrong
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : C9orf72-SMCR8 complex

EntireName: C9orf72-SMCR8 complex
Components
  • Complex: C9orf72-SMCR8 complex
    • Protein or peptide: Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72
    • Protein or peptide: Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exchange protein SMCR8,Maltose/maltodextrin-binding periplasmic protein

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Supramolecule #1: C9orf72-SMCR8 complex

SupramoleculeName: C9orf72-SMCR8 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 201 KDa

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Macromolecule #1: Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72

MacromoleculeName: Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.167727 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAHHHHHHGS DSEVNQEAKP EVKPEVKPET HINLKVSDGS SEIFFKIKKT TPLRRLMEAF AKRQGKEMDS LRFLYDGIRI QADQTPEDL DMEDNDIIEA HREQISSGLD AAAMSTLCPP PSPAVAKTEI ALSGKSPLLA ATFAYWDNIL GPRVRHIWAP K TEQVLLSD ...String:
MAHHHHHHGS DSEVNQEAKP EVKPEVKPET HINLKVSDGS SEIFFKIKKT TPLRRLMEAF AKRQGKEMDS LRFLYDGIRI QADQTPEDL DMEDNDIIEA HREQISSGLD AAAMSTLCPP PSPAVAKTEI ALSGKSPLLA ATFAYWDNIL GPRVRHIWAP K TEQVLLSD GEITFLANHT LNGEILRNAE SGAIDVKFFV LSEKGVIIVS LIFDGNWNGD RSTYGLSIIL PQTELSFYLP LH RVCVDRL THIIRKGRIW MHKERQENVQ KIILEGTERM EDQGQSIIPM LTGEVIPVME LLSSMKSHSV PEEIDIADTV LND DDIGDS CHEGFLLNAI SSHLQTCGCS VVVGSSAEKV NKIVRTLCLF LTPAERKCSR LCEAESSFKY ESGLFVQGLL KDST GSFVL PFRQVMYAPY PTTHIDVDVN TVKQMPPCHE HIYNQRRYMR SELTAFWRAT SEEDMAQDTI IYTDESFTPD LNIFQ DVLH RDTLVKAFLD QVFQLKPGLS LRSTFLAQFL LVLHRKALTL IKYIEDDTQK GKKPFKSLRN LKIDLDLTAE GDLNII MAL AEKIKPGLHS FIFGRPFYTS VQERDVLMTF

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Macromolecule #2: Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exch...

MacromoleculeName: Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exchange protein SMCR8,Maltose/maltodextrin-binding periplasmic protein
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli K-12 (bacteria)
Molecular weightTheoretical: 134.389406 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDSAWSHPQF EKGGGSGGGS GGSAWSHPQF EKSAVDLEVL FQGPGMISAP DVVAFTKEEE YEEEPYNEPA LPEEYSVPLF PFASQGANP WSKLSGAKFS RDFILISEFS EQVGPQPLLT IPNDTKVFGT FDLNYFSLRI MSVDYQASFV GHPPGSAYPK L NFVEDSKV ...String:
MDSAWSHPQF EKGGGSGGGS GGSAWSHPQF EKSAVDLEVL FQGPGMISAP DVVAFTKEEE YEEEPYNEPA LPEEYSVPLF PFASQGANP WSKLSGAKFS RDFILISEFS EQVGPQPLLT IPNDTKVFGT FDLNYFSLRI MSVDYQASFV GHPPGSAYPK L NFVEDSKV VLGDSKEGAF AYVHHLTLYD LEARGFVRPF CMAYISADQH KIMQQFQELS AEFSRASECL KTGNRKAFAG EL EKKLKDL DYTRTVLHTE TEIQKKANDK GFYSSQAIEK ANELASVEKS IIEHQDLLKQ IRSYPHRKLK GHDLCPGEME HIQ DQASQA STTSNPDESA DTDLYTCRPA YTPKLIKAKS TKCFDKKLKT LEELCDTEYF TQTLAQLSHI EHMFRGDLCY LLTS QIDRA LLKQQHITNF LFEDFVEVDD RMVEKQESIP SKPSQDRPPS SSLEECPIPK VLISVGSYKS SVESVLIKME QELGD EEYK DTGSTGSTSG TLEVLFQGPG RQKDQGFRVD FSVENANPSS RDNSCEGFPA YELDPSHLLA SRDISKTSLD NYSDTT SYV SSVASTSSDR IPSAYPAGLS SDRHKKRAGQ NALKFIRQYP FAHPAIYSLL SGRTLVVLGE DEAIVRKLVT ALAIFVP SY GCYAKPVKHW ASSPLHIMDF QKWKLIGLQR VASPAGAGTL HALSRYSRYT SILDLDNKTL RCPLYRGTLV PRLADHRT Q IKRGSTYYLH VQSMLTQLCS KAFLYTFCHH LHLPTHDKET EELVASRQMS FLKLTLGLVN EDVRVVQYLA ELLKLHYMQ ESPGTSHPML RFDYVPSFLY KIGGSGSENL YFQGGTSSGM KIEEGKLVIW INGDKGYNGL AEVGKKFEKD TGIKVTVEHP DKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDKL YPFTWDAVRY NGKLIAYPIA VEALSLIYNK D LLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW PLIAADGGYA FKYENGKYDI KDVGVDNAGA KAGLTFLVDL IK NKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SKVNYGVTVL PTFKGQPSKP FVGVLSAGIN AASPNKELAK EFL ENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAATMENAQK GEIMPNIPQM SAFWYAVRTA VINAASGRQT VDEA LKDAQ T

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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

Concentration0.37 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionNumber images used: 284568

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