+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-12700 | |||||||||
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Title | Structure of the C9orf72-SMCR8 complex | |||||||||
Map data | Map of C9orf72-SMCR8 complex | |||||||||
Sample |
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Keywords | Denn domain / Coiled-coil / GTPase-activating protein / PROTEIN BINDING | |||||||||
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) / SUMO is proteolytically processed / late endosome to lysosome transport / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / regulation of TORC1 signaling ...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) / SUMO is proteolytically processed / late endosome to lysosome transport / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / regulation of TORC1 signaling / septin ring / SUMOylation of DNA damage response and repair proteins / negative regulation of autophagosome assembly / regulation of actin filament organization / SUMOylation of DNA replication proteins / guanyl-nucleotide exchange factor complex / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / negative regulation of immune response / regulation of autophagosome assembly / SUMOylation of SUMOylation proteins / SUMOylation of RNA binding proteins / SUMOylation of chromatin organization proteins / Flemming body / presynaptic cytosol / axon extension / negative regulation of exocytosis / positive regulation of autophagosome maturation / main axon / negative regulation of macroautophagy / detection of maltose stimulus / protein kinase inhibitor activity / maltose transport complex / ubiquitin-like protein ligase binding / carbohydrate transport / positive regulation of macroautophagy / maltose binding / protein sumoylation / maltose transport / maltodextrin transmembrane transport / carbohydrate transmembrane transporter activity / positive regulation of TOR signaling / axonal growth cone / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / stress granule assembly / autophagosome / GTPase activator activity / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / negative regulation of protein phosphorylation / guanyl-nucleotide exchange factor activity / positive regulation of GTPase activity / condensed nuclear chromosome / cell projection / regulation of autophagy / P-body / small GTPase binding / autophagy / cytoplasmic stress granule / endocytosis / protein tag activity / regulation of protein localization / presynapse / outer membrane-bounded periplasmic space / nuclear membrane / perikaryon / postsynapse / periplasmic space / lysosome / endosome / intracellular membrane-bounded organelle / negative regulation of gene expression / DNA damage response / dendrite / chromatin / protein kinase binding / extracellular space / nucleoplasm / identical protein binding / membrane / nucleus / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Escherichia coli K-12 (bacteria) | |||||||||
Method | single particle reconstruction / cryo EM | |||||||||
Authors | Noerpel J / Cavadini S | |||||||||
Funding support | Switzerland, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_12700.map.gz | 5.4 MB | EMDB map data format | |
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Header (meta data) | emd-12700-v30.xml emd-12700.xml | 16.3 KB 16.3 KB | Display Display | EMDB header |
Images | emd_12700.png | 35.7 KB | ||
Filedesc metadata | emd-12700.cif.gz | 6.5 KB | ||
Others | emd_12700_additional_1.map.gz emd_12700_additional_2.map.gz | 65.3 MB 65.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-12700 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12700 | HTTPS FTP |
-Validation report
Summary document | emd_12700_validation.pdf.gz | 334.7 KB | Display | EMDB validaton report |
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Full document | emd_12700_full_validation.pdf.gz | 334.3 KB | Display | |
Data in XML | emd_12700_validation.xml.gz | 6.2 KB | Display | |
Data in CIF | emd_12700_validation.cif.gz | 7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12700 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12700 | HTTPS FTP |
-Related structure data
Related structure data | 7o2wMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_12700.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Map of C9orf72-SMCR8 complex | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.86 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: Unsharpened map of C9orf72-SMCR8 complex
File | emd_12700_additional_1.map | ||||||||||||
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Annotation | Unsharpened map of C9orf72-SMCR8 complex | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Unsharpened map of C9orf72-SMCR8 complex at 4.3 angstrong
File | emd_12700_additional_2.map | ||||||||||||
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Annotation | Unsharpened map of C9orf72-SMCR8 complex at 4.3 angstrong | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : C9orf72-SMCR8 complex
Entire | Name: C9orf72-SMCR8 complex |
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Components |
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-Supramolecule #1: C9orf72-SMCR8 complex
Supramolecule | Name: C9orf72-SMCR8 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 201 KDa |
-Macromolecule #1: Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72
Macromolecule | Name: Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 67.167727 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 UniProtKB: Ubiquitin-like protein SMT3, Guanine nucleotide exchange factor C9orf72 |
-Macromolecule #2: Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exch...
Macromolecule | Name: 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 |
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Source (natural) | Organism: Escherichia coli K-12 (bacteria) |
Molecular weight | Theoretical: 134.389406 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 UniProtKB: Guanine nucleotide exchange protein SMCR8, Guanine nucleotide exchange protein SMCR8, Maltose/maltodextrin-binding periplasmic protein |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.37 mg/mL |
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Buffer | pH: 8 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Number images used: 284568 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |