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- EMDB-21048: Cryo-EM structure of SMCR8-C9orf72-WDR41 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-21048
TitleCryo-EM structure of SMCR8-C9orf72-WDR41 complex
Map datastructure of L-SCARF complex (SMCR8-C9orf72-WDR41)
Sample
  • Complex: Complex of SMCR8-C9orf72-WDR41
    • Protein or peptide: WD repeat-containing protein 41
    • Protein or peptide: Guanine nucleotide exchange C9orf72
    • Protein or peptide: Guanine nucleotide exchange protein SMCR8
KeywordsComplex / trimer / autophagy / TRANSPORT PROTEIN
Function / homology
Function and homology information


Atg1/ULK1 kinase complex / late endosome to lysosome transport / regulation of TORC1 signaling / regulation of autophagosome assembly / negative regulation of autophagosome assembly / regulation of actin filament organization / guanyl-nucleotide exchange factor complex / negative regulation of immune response / axon extension / Flemming body ...Atg1/ULK1 kinase complex / late endosome to lysosome transport / regulation of TORC1 signaling / regulation of autophagosome assembly / negative regulation of autophagosome assembly / regulation of actin filament organization / guanyl-nucleotide exchange factor complex / negative regulation of immune response / axon extension / Flemming body / negative regulation of exocytosis / positive regulation of autophagosome maturation / main axon / negative regulation of macroautophagy / protein kinase inhibitor activity / positive regulation of macroautophagy / positive regulation of TOR signaling / autophagosome / axonal growth cone / stress granule assembly / GTPase activator activity / guanyl-nucleotide exchange factor activity / positive regulation of GTPase activity / negative regulation of protein phosphorylation / regulation of autophagy / cell projection / negative regulation of protein kinase activity / P-body / small GTPase binding / autophagy / cytoplasmic stress granule / endocytosis / regulation of protein localization / presynapse / postsynapse / perikaryon / nuclear membrane / lysosome / endosome / lysosomal membrane / negative regulation of gene expression / intracellular membrane-bounded organelle / dendrite / chromatin / protein kinase binding / extracellular space / nucleoplasm / nucleus / cytoplasm / cytosol
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. / G-protein beta WD-40 repeat / WD40 repeat, conserved site ...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. / 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. / WD domain, G-beta repeat / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsSu MY / Hurley JH
Funding support United States, 2 items
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, 2019-
Header (metadata) releaseSep 2, 2020-
Map releaseSep 2, 2020-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.422
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.422
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6v4u
  • Surface level: 0.422
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21048.png

Downloads & links

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Map

FileDownload / File: emd_21048.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of L-SCARF complex (SMCR8-C9orf72-WDR41)
Voxel sizeX=Y=Z: 1.1492 Å
Density
Contour LevelBy AUTHOR: 0.422 / Movie #1: 0.422
Minimum - Maximum-0.88440055 - 1.5180515
Average (Standard dev.)0.002345376 (±0.03871994)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 275.80798 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.14921.14921.1492
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z275.808275.808275.808
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.8841.5180.002

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Supplemental data

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Sample components

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Entire : Complex of SMCR8-C9orf72-WDR41

EntireName: Complex of SMCR8-C9orf72-WDR41
Components
  • Complex: Complex of SMCR8-C9orf72-WDR41
    • Protein or peptide: WD repeat-containing protein 41
    • Protein or peptide: Guanine nucleotide exchange C9orf72
    • Protein or peptide: Guanine nucleotide exchange protein SMCR8

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Supramolecule #1: Complex of SMCR8-C9orf72-WDR41

SupramoleculeName: Complex of SMCR8-C9orf72-WDR41 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 120 KDa

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Macromolecule #1: WD repeat-containing protein 41

MacromoleculeName: WD repeat-containing protein 41 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.783805 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLRWLIGGGR EPQGLAEKSP LQTIGEEQTQ NPYTELLVLK AHHDIVRFLV QLDDYRFASA GDDGIVVVWN AQTGEKLLEL NGHTQKITA IITFPSLESC EEKNQLILTA SADRTVIVWD GDTTRQVQRI SCFQSTVKCL TVLQRLDVWL SGGNDLCVWN R KLDLLCKT ...String:
MLRWLIGGGR EPQGLAEKSP LQTIGEEQTQ NPYTELLVLK AHHDIVRFLV QLDDYRFASA GDDGIVVVWN AQTGEKLLEL NGHTQKITA IITFPSLESC EEKNQLILTA SADRTVIVWD GDTTRQVQRI SCFQSTVKCL TVLQRLDVWL SGGNDLCVWN R KLDLLCKT SHLSDTGISA LVEIPKNCVV AAVGKELIIF RLVAPTEGSL EWDILEVKRL LDHQDNILSL INVNDLSFVT GS HVGELII WDALDWTMQA YERNFWDPSP QLDTQQEIKL CQKSNDISIH HFTCDEENVF AAVGRGLYVY SLQMKRVIAC QKT AHDSNV LHVARLPNRQ LISCSEDGSV RIWELREKQQ LAAEPVPTGF FNMWGFGRVS KQASQPVKKQ QENATSCSLE LIGD LIGHS SSVEMFLYFE DHGLVTCSAD HLIILWKNGE RESGLRSLRL FQKLEENGDL YLAV

UniProtKB: WD repeat-containing protein 41

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Macromolecule #2: Guanine nucleotide exchange C9orf72

MacromoleculeName: Guanine nucleotide exchange C9orf72 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.391477 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSTLCPPPSP AVAKTEIALS GKSPLLAATF AYWDNILGPR VRHIWAPKTE QVLLSDGEIT FLANHTLNGE ILRNAESGAI DVKFFVLSE KGVIIVSLIF DGNWNGDRST YGLSIILPQT ELSFYLPLHR VCVDRLTHII RKGRIWMHKE RQENVQKIIL E GTERMEDQ ...String:
MSTLCPPPSP AVAKTEIALS GKSPLLAATF AYWDNILGPR VRHIWAPKTE QVLLSDGEIT FLANHTLNGE ILRNAESGAI DVKFFVLSE KGVIIVSLIF DGNWNGDRST YGLSIILPQT ELSFYLPLHR VCVDRLTHII RKGRIWMHKE RQENVQKIIL E GTERMEDQ GQSIIPMLTG EVIPVMELLS SMKSHSVPEE IDIADTVLND DDIGDSCHEG FLLNAISSHL QTCGCSVVVG SS AEKVNKI VRTLCLFLTP AERKCSRLCE AESSFKYESG LFVQGLLKDS TGSFVLPFRQ VMYAPYPTTH IDVDVNTVKQ MPP CHEHIY NQRRYMRSEL TAFWRATSEE DMAQDTIIYT DESFTPDLNI FQDVLHRDTL VKAFLDQVFQ LKPGLSLRST FLAQ FLLVL HRKALTLIKY IEDDTQKGKK PFKSLRNLKI DLDLTAEGDL NIIMALAEKI KPGLHSFIFG RPFYTSVQER DVLMT F

UniProtKB: Guanine nucleotide exchange factor C9orf72

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Macromolecule #3: Guanine nucleotide exchange protein SMCR8

MacromoleculeName: Guanine nucleotide exchange protein SMCR8 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 105.149094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MISAPDVVAF TKEEEYEEEP YNEPALPEEY SVPLFPFASQ GANPWSKLSG AKFSRDFILI SEFSEQVGPQ PLLTIPNDTK VFGTFDLNY FSLRIMSVDY QASFVGHPPG SAYPKLNFVE DSKVVLGDSK EGAFAYVHHL TLYDLEARGF VRPFCMAYIS A DQHKIMQQ ...String:
MISAPDVVAF TKEEEYEEEP YNEPALPEEY SVPLFPFASQ GANPWSKLSG AKFSRDFILI SEFSEQVGPQ PLLTIPNDTK VFGTFDLNY FSLRIMSVDY QASFVGHPPG SAYPKLNFVE DSKVVLGDSK EGAFAYVHHL TLYDLEARGF VRPFCMAYIS A DQHKIMQQ FQELSAEFSR ASECLKTGNR KAFAGELEKK LKDLDYTRTV LHTETEIQKK ANDKGFYSSQ AIEKANELAS VE KSIIEHQ DLLKQIRSYP HRKLKGHDLC PGEMEHIQDQ ASQASTTSNP DESADTDLYT CRPAYTPKLI KAKSTKCFDK KLK TLEELC DTEYFTQTLA QLSHIEHMFR GDLCYLLTSQ IDRALLKQQH ITNFLFEDFV EVDDRMVEKQ ESIPSKPSQD RPPS SSLEE CPIPKVLISV GSYKSSVESV LIKMEQELGD EEYKEVEVTE LSSFDPQENL DYLDMDMKGS ISSGESIEVL GTEKS TSVL SKSDSQASLT VPLSPQVVRS KAVSHRTISE DSIEVLSTCP SEALIPDDFK ASYPSAINEE ESYPDGNEGA IRFQAS ISP PELGETEEGS IENTPSQIDS SCCIGKESDG QLVLPSTPAH THSDEDGVVS SPPQRHRQKD QGFRVDFSVE NANPSSR DN SCEGFPAYEL DPSHLLASRD ISKTSLDNYS DTTSYVSSVA STSSDRIPSA YPAGLSSDRH KKRAGQNALK FIRQYPFA H PAIYSLLSGR TLVVLGEDEA IVRKLVTALA IFVPSYGCYA KPVKHWASSP LHIMDFQKWK LIGLQRVASP AGAGTLHAL SRYSRYTSIL DLDNKTLRCP LYRGTLVPRL ADHRTQIKRG STYYLHVQSM LTQLCSKAFL YTFCHHLHLP THDKETEELV ASRQMSFLK LTLGLVNEDV RVVQYLAELL KLHYMQESPG TSHPMLRFDY VPSFLYKI

UniProtKB: Guanine nucleotide exchange protein SMCR8

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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

Concentration0.17 mg/mL
BufferpH: 7.4
GridModel: C-flat-1.2/1.3 / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Number real images: 3508 / Average electron dose: 59.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4810184
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF
Software: (Name: cryoSPARC (ver. v2), RELION (ver. 3.0-beta))
Number images used: 381450
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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Atomic model buiding 1

Initial model
PDB IDChain

6nzd

chain_id: H, source_name: PDB, initial_model_type: experimental model

6nzd

chain_id: I, source_name: PDB, initial_model_type: experimental model

6ces

source_name: PDB, initial_model_type: experimental model

3tw8

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

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

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