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- PDB-7o2w: Structure of the C9orf72-SMCR8 complex -

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Basic information

Entry
Database: PDB / ID: 7o2w
TitleStructure of the C9orf72-SMCR8 complex
Components
  • Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exchange protein SMCR8,Maltose/maltodextrin-binding periplasmic protein
  • Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72
KeywordsPROTEIN BINDING / Denn domain / Coiled-coil / GTPase-activating 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) / late endosome to lysosome transport / SUMO is proteolytically processed / SUMOylation of transcription factors / SUMOylation of transcription cofactors / negative regulation of immune response / 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) / late endosome to lysosome transport / SUMO is proteolytically processed / SUMOylation of transcription factors / SUMOylation of transcription cofactors / negative regulation of immune response / regulation of TORC1 signaling / Postmitotic nuclear pore complex (NPC) reformation / autophagosome-lysosome fusion / septin ring / SUMOylation of DNA damage response and repair proteins / regulation of actin filament organization / Transcriptional and post-translational regulation of MITF-M expression and activity / guanyl-nucleotide exchange factor complex / negative regulation of autophagosome assembly / SUMOylation of DNA replication proteins / regulation of autophagosome assembly / SUMOylation of SUMOylation proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Flemming body / SUMOylation of RNA binding proteins / regulation of synaptic vesicle cycle / axon extension / positive regulation of autophagosome maturation / SUMOylation of chromatin organization proteins / negative regulation of exocytosis / negative regulation of macroautophagy / detection of maltose stimulus / maltose transport complex / protein kinase inhibitor activity / negative regulation of protein phosphorylation / carbohydrate transport / ubiquitin-like protein ligase binding / positive regulation of macroautophagy / protein sumoylation / main axon / carbohydrate transmembrane transporter activity / maltose binding / positive regulation of TOR signaling / maltose transport / maltodextrin transmembrane transport / axonal growth cone / presynaptic cytosol / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / stress granule assembly / ATP-binding cassette (ABC) transporter complex / GTPase activator activity / autophagosome / guanyl-nucleotide exchange factor activity / hippocampal mossy fiber to CA3 synapse / condensed nuclear chromosome / cell chemotaxis / cell projection / P-body / small GTPase binding / autophagy / protein tag activity / endocytosis / cytoplasmic stress granule / presynapse / regulation of protein localization / outer membrane-bounded periplasmic space / perikaryon / nuclear membrane / periplasmic space / lysosome / postsynapse / endosome / regulation of autophagy / negative regulation of gene expression / intracellular membrane-bounded organelle / dendrite / DNA damage response / protein kinase binding / chromatin / glutamatergic synapse / extracellular space / nucleoplasm / identical protein binding / nucleus / membrane / cytoplasm / cytosol
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 domain profile. / Ubiquitin-like domain / 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 speciesSaccharomyces cerevisiae S288c (yeast)
Homo sapiens (human)
Escherichia coli K-12 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsNoerpel, J. / Cavadini, S. / Schenk, A.D. / Graff-Meyer, A. / Chao, J. / Bhaskar, V.
Funding support Switzerland, 1items
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, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 21, 2021Provider: repository / Type: Initial release
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Revision 1.1Feb 2, 2022Group: Database references / Category: citation / citation_author / database_2
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Revision 1.2Jul 10, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update
Revision 1.3Apr 2, 2025Group: Data collection / Data processing / Structure summary
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Assembly

Deposited unit
A: Ubiquitin-like protein SMT3,Guanine nucleotide exchange C9orf72
B: Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exchange protein SMCR8,Maltose/maltodextrin-binding periplasmic protein


Theoretical massNumber of molelcules
Total (without water)201,5572
Polymers201,5572
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area4630 Å2
ΔGint-34 kcal/mol
Surface area42110 Å2
MethodPISA

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Components

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


Mass: 67167.727 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae S288c (yeast), (gene. exp.) Homo sapiens (human)
Gene: SMT3, YDR510W, D9719.15, C9orf72 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q12306, UniProt: Q96LT7
#2: Protein Guanine nucleotide exchange protein SMCR8,Guanine nucleotide exchange protein SMCR8,Maltose/maltodextrin-binding periplasmic protein / Smith-Magenis syndrome chromosomal region candidate gene 8 protein / Smith-Magenis syndrome ...Smith-Magenis syndrome chromosomal region candidate gene 8 protein / Smith-Magenis syndrome chromosomal region candidate gene 8 protein / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP


Mass: 134389.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli K-12 (bacteria)
Gene: SMCR8, malE, b4034, JW3994 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8TEV9, UniProt: P0AEX9
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: C9orf72-SMCR8 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.201 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 0.37 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 284568 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0066573
ELECTRON MICROSCOPYf_angle_d0.9338923
ELECTRON MICROSCOPYf_dihedral_angle_d20.537893
ELECTRON MICROSCOPYf_chiral_restr0.051049
ELECTRON MICROSCOPYf_plane_restr0.0051121

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