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- PDB-6v4u: Cryo-EM structure of SMCR8-C9orf72-WDR41 complex -

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Basic information

Entry
Database: PDB / ID: 6v4u
TitleCryo-EM structure of SMCR8-C9orf72-WDR41 complex
Components
  • Guanine nucleotide exchange C9orf72
  • Guanine nucleotide exchange protein SMCR8
  • WD repeat-containing protein 41
KeywordsTRANSPORT PROTEIN / Complex / trimer / autophagy
Function / homology
Function and homology information


Atg1/ULK1 kinase complex / late endosome to lysosome transport / regulation of TORC1 signaling / negative regulation of immune response / autophagosome-lysosome fusion / regulation of actin filament organization / guanyl-nucleotide exchange factor complex / negative regulation of autophagosome assembly / regulation of autophagosome assembly / Flemming body ...Atg1/ULK1 kinase complex / late endosome to lysosome transport / regulation of TORC1 signaling / negative regulation of immune response / autophagosome-lysosome fusion / regulation of actin filament organization / guanyl-nucleotide exchange factor complex / negative regulation of autophagosome assembly / regulation of autophagosome assembly / Flemming body / regulation of synaptic vesicle cycle / axon extension / positive regulation of autophagosome maturation / negative regulation of exocytosis / negative regulation of macroautophagy / protein kinase inhibitor activity / negative regulation of protein phosphorylation / positive regulation of macroautophagy / main axon / positive regulation of TOR signaling / axonal growth cone / presynaptic cytosol / stress granule assembly / GTPase activator activity / autophagosome / guanyl-nucleotide exchange factor activity / hippocampal mossy fiber to CA3 synapse / cell projection / P-body / small GTPase binding / autophagy / endocytosis / cytoplasmic stress granule / presynapse / regulation of protein localization / nuclear membrane / perikaryon / lysosome / postsynapse / endosome / regulation of autophagy / negative regulation of gene expression / lysosomal membrane / intracellular membrane-bounded organelle / dendrite / protein kinase binding / chromatin / glutamatergic synapse / extracellular space / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
WD repeat-containing protein 41 / WDR41 / 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. / WD domain, G-beta repeat ...WD repeat-containing protein 41 / WDR41 / 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. / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Guanine nucleotide exchange protein SMCR8 / Guanine nucleotide exchange factor C9orf72 / WD repeat-containing protein 41
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsSu, M.Y. / Hurley, J.H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01GM111730 United States
Department of Defense (DOD, United States)W81XWH2010086 United States
CitationJournal: Nature / Year: 2020
Title: Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD.
Authors: Ming-Yuan Su / Simon A Fromm / Roberto Zoncu / James H Hurley /
Abstract: Mutation of C9orf72 is the most prevalent defect associated with amyotrophic lateral sclerosis and frontotemporal degeneration. Together with hexanucleotide-repeat expansion, haploinsufficiency of ...Mutation of C9orf72 is the most prevalent defect associated with amyotrophic lateral sclerosis and frontotemporal degeneration. Together with hexanucleotide-repeat expansion, haploinsufficiency of C9orf72 contributes to neuronal dysfunction. Here we determine the structure of the C9orf72-SMCR8-WDR41 complex by cryo-electron microscopy. C9orf72 and SMCR8 both contain longin and DENN (differentially expressed in normal and neoplastic cells) domains, and WDR41 is a β-propeller protein that binds to SMCR8 such that the whole structure resembles an eye slip hook. Contacts between WDR41 and the DENN domain of SMCR8 drive the lysosomal localization of the complex in conditions of amino acid starvation. The structure suggested that C9orf72-SMCR8 is a GTPase-activating protein (GAP), and we found that C9orf72-SMCR8-WDR41 acts as a GAP for the ARF family of small GTPases. These data shed light on the function of C9orf72 in normal physiology, and in amyotrophic lateral sclerosis and frontotemporal degeneration.
History
DepositionDec 1, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2020Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 2, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2020Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 23, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type
Revision 1.4May 14, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 14, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
C: WD repeat-containing protein 41
A: Guanine nucleotide exchange C9orf72
B: Guanine nucleotide exchange protein SMCR8


Theoretical massNumber of molelcules
Total (without water)211,3243
Polymers211,3243
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Superose 6 column
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein WD repeat-containing protein 41


Mass: 51783.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR41, MSTP048 / Cell line (production host): HEK293GnTi / Production host: Homo sapiens (human) / References: UniProt: Q9HAD4
#2: Protein Guanine nucleotide exchange C9orf72


Mass: 54391.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C9orf72 / Cell line (production host): HEK293GnTi / Production host: Homo sapiens (human) / References: UniProt: Q96LT7
#3: Protein Guanine nucleotide exchange protein SMCR8 / Smith-Magenis syndrome chromosomal region candidate gene 8 protein


Mass: 105149.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMCR8 / Cell line (production host): HEK293GnTi / Production host: Homo sapiens (human) / References: UniProt: Q8TEV9
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: Complex of SMCR8-C9orf72-WDR41 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.12 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 0.17 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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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: OTHER
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 59.8 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 3508

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEM3.6.14image acquisition
4Gctf1.06CTF correction
7Coot0.9model fitting
8Coot0.8.9.1model fitting
13cryoSPARCv23D reconstruction
14RELION3.0-beta3D reconstruction
15PHENIXmodel refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 4810184
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 381450 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeInitial refinement model-ID
16NZD

6nzd

H6NZD1
26NZD

6nzd

I6NZD1
36CES

6ces

6CES2
43TW8

3tw8

3TW83
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0017167
ELECTRON MICROSCOPYf_angle_d0.4519817
ELECTRON MICROSCOPYf_dihedral_angle_d3.1474166
ELECTRON MICROSCOPYf_chiral_restr0.0411226
ELECTRON MICROSCOPYf_plane_restr0.0031294

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