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- PDB-7mge: Structure of C9orf72:SMCR8:WDR41 in complex with ARF1 -

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Basic information

Entry
Database: PDB / ID: 7mge
TitleStructure of C9orf72:SMCR8:WDR41 in complex with ARF1
Components
  • (Guanine nucleotide exchange ...) x 2
  • ADP-ribosylation factor 1ARF1
  • WD repeat-containing protein 41
KeywordsTRANSPORT PROTEIN / complex / autophagy / ALS / GAP / small GTPase
Function / homology
Function and homology information


mitotic cleavage furrow ingression / trans-Golgi Network Vesicle Budding / Atg1/ULK1 kinase complex / regulation of receptor internalization / regulation of Arp2/3 complex-mediated actin nucleation / late endosome to lysosome transport / Intra-Golgi traffic / regulation of TORC1 signaling / Synthesis of PIPs at the Golgi membrane / regulation of autophagosome assembly ...mitotic cleavage furrow ingression / trans-Golgi Network Vesicle Budding / Atg1/ULK1 kinase complex / regulation of receptor internalization / regulation of Arp2/3 complex-mediated actin nucleation / late endosome to lysosome transport / Intra-Golgi traffic / regulation of TORC1 signaling / Synthesis of PIPs at the Golgi membrane / regulation of autophagosome assembly / negative regulation of autophagosome assembly / regulation of actin filament organization / guanyl-nucleotide exchange factor complex / negative regulation of immune response / Nef Mediated CD4 Down-regulation / dendritic spine organization / axon extension / negative regulation of exocytosis / Flemming body / positive regulation of autophagosome maturation / long-term synaptic depression / COPI-dependent Golgi-to-ER retrograde traffic / main axon / Lysosome Vesicle Biogenesis / negative regulation of macroautophagy / Golgi Associated Vesicle Biogenesis / protein kinase inhibitor activity / cell leading edge / Synthesis of PIPs at the plasma membrane / positive regulation of macroautophagy / intracellular copper ion homeostasis / autophagosome / positive regulation of TOR signaling / COPI-mediated anterograde transport / axonal growth cone / stress granule assembly / vesicle-mediated transport / MHC class II antigen presentation / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / GTPase activator activity / sarcomere / guanyl-nucleotide exchange factor activity / small monomeric GTPase / negative regulation of protein phosphorylation / cell projection / regulation of autophagy / P-body / intracellular protein transport / negative regulation of protein kinase activity / small GTPase binding / cellular response to virus / positive regulation of GTPase activity / autophagy / cytoplasmic stress granule / endocytosis / regulation of protein localization / presynapse / perikaryon / postsynapse / nuclear membrane / postsynaptic density / lysosome / endosome / neuron projection / lysosomal membrane / protein domain specific binding / Golgi membrane / negative regulation of gene expression / focal adhesion / intracellular membrane-bounded organelle / GTPase activity / dendrite / chromatin / GTP binding / protein kinase binding / magnesium ion binding / protein-containing complex / extracellular space / RNA binding / extracellular exosome / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
WD repeat-containing protein 41 / 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. / ADP-ribosylation factor 1-5 / small GTPase Arf family profile. ...WD repeat-containing protein 41 / 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. / ADP-ribosylation factor 1-5 / small GTPase Arf family profile. / Sar1p-like members of the Ras-family of small GTPases / Small GTPase superfamily, ARF/SAR type / ADP-ribosylation factor family / ARF-like small GTPases; ARF, ADP-ribosylation factor / Rab subfamily of small GTPases / Small GTP-binding protein domain / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
BERYLLIUM TRIFLUORIDE ION / GUANOSINE-5'-DIPHOSPHATE / ADP-ribosylation factor 1 / 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: 3.94 Å
AuthorsSu, M.-Y. / Hurley, J.H.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Defense (DOD, United States)W81XWH2010086 United States
CitationJournal: Nat Commun / Year: 2021
Title: Structural basis for the ARF GAP activity and specificity of the C9orf72 complex.
Authors: Ming-Yuan Su / Simon A Fromm / Jonathan Remis / Daniel B Toso / James H Hurley /
Abstract: Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 ...Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF bound to C9orf72:SMCR8:WDR41. The SMCR8 and C9orf72 domains form the binding pocket for ARF1. One face of the C9orf72 domain holds ARF1 in place, while the SMCR8 positions the catalytic finger Arg147 in the ARF1 active site. Mutations in interfacial residues of ARF1 and C9orf72 reduced or eliminated GAP activity. RAB8A GAP required ~10-fold higher concentrations of the C9orf72 complex than for ARF1. These data support a specific function for the C9orf72 complex as an ARF GAP. The structure also provides a model for the active forms of the longin domain GAPs of FLCN and NPRL2 that regulate the Rag GTPases of the mTORC1 pathway.
History
DepositionApr 12, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

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  • Deposited structure unit
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  • EMDB-23827
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Assembly

Deposited unit
A: WD repeat-containing protein 41
B: Guanine nucleotide exchange protein SMCR8
C: Guanine nucleotide exchange C9orf72
E: ADP-ribosylation factor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,8527
Polymers230,3194
Non-polymers5343
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, superose 6 column
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8900 Å2
ΔGint-71 kcal/mol
Surface area70660 Å2

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Components

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Protein , 2 types, 2 molecules AE

#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): HEK 293 GnTi / Production host: Homo sapiens (human) / References: UniProt: Q9HAD4
#4: Protein ADP-ribosylation factor 1 / ARF1


Mass: 18994.572 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARF1 / Cell line (production host): HEK 293 GnTi / Production host: Homo sapiens (human) / References: UniProt: P84077

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Guanine nucleotide exchange ... , 2 types, 2 molecules BC

#2: 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): HEK 293 GnTi / Production host: Homo sapiens (human) / References: UniProt: Q8TEV9
#3: 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): HEK 293 GnTi / Production host: Homo sapiens (human) / References: UniProt: Q96LT7

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Non-polymers , 3 types, 3 molecules

#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#6: Chemical ChemComp-BEF / BERYLLIUM TRIFLUORIDE ION


Mass: 66.007 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: BeF3
#7: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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Details

Has ligand of interestN

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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 C9orf72:SMCR8:WDR41 with ARF1 / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightUnits: MEGADALTONS / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 0.16 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: concentration range of 0.16-0.2 mg/ml
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: 277 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 FIELDBright-field microscopy
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
EM softwareName: SerialEM / Category: image acquisition
CTF correctionType: NONE
3D reconstructionResolution: 3.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 796219 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039164
ELECTRON MICROSCOPYf_angle_d0.65412511
ELECTRON MICROSCOPYf_dihedral_angle_d5.1991365
ELECTRON MICROSCOPYf_chiral_restr0.0441520
ELECTRON MICROSCOPYf_plane_restr0.0041611

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