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- EMDB-23930: Neurofibromin homodimer -

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Basic information

Entry
Database: EMDB / ID: EMD-23930
TitleNeurofibromin homodimer
Map data
Sample
  • Complex: Neurofibromin homodimer
    • Protein or peptide: Isoform I of Neurofibromin
Function / homology
Function and homology information


positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / gamma-aminobutyric acid secretion, neurotransmission / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / mast cell apoptotic process ...positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / gamma-aminobutyric acid secretion, neurotransmission / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / mast cell apoptotic process / negative regulation of mast cell proliferation / Schwann cell proliferation / vascular associated smooth muscle cell proliferation / mast cell proliferation / glutamate secretion, neurotransmission / negative regulation of Schwann cell proliferation / negative regulation of leukocyte migration / negative regulation of vascular associated smooth muscle cell migration / positive regulation of adenylate cyclase activity / forebrain morphogenesis / regulation of cell-matrix adhesion / negative regulation of neurotransmitter secretion / hair follicle maturation / regulation of blood vessel endothelial cell migration / cell communication / camera-type eye morphogenesis / smooth muscle tissue development / negative regulation of oligodendrocyte differentiation / myelination in peripheral nervous system / sympathetic nervous system development / phosphatidylcholine binding / myeloid leukocyte migration / phosphatidylethanolamine binding / peripheral nervous system development / metanephros development / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / endothelial cell proliferation / artery morphogenesis / collagen fibril organization / regulation of bone resorption / regulation of long-term synaptic potentiation / neural tube development / regulation of postsynapse organization / forebrain astrocyte development / pigmentation / negative regulation of neuroblast proliferation / regulation of synaptic transmission, GABAergic / adrenal gland development / negative regulation of protein import into nucleus / negative regulation of cell-matrix adhesion / spinal cord development / regulation of GTPase activity / negative regulation of endothelial cell proliferation / negative regulation of MAPK cascade / Rac protein signal transduction / oligodendrocyte differentiation / negative regulation of osteoclast differentiation / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of astrocyte differentiation / neuroblast proliferation / extrinsic apoptotic signaling pathway via death domain receptors / regulation of angiogenesis / Schwann cell development / skeletal muscle tissue development / negative regulation of fibroblast proliferation / negative regulation of stem cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / GTPase activator activity / extracellular matrix organization / negative regulation of angiogenesis / osteoclast differentiation / regulation of ERK1 and ERK2 cascade / negative regulation of MAP kinase activity / negative regulation of cell migration / liver development / phosphatidylinositol 3-kinase/protein kinase B signal transduction / long-term synaptic potentiation / stem cell proliferation / regulation of long-term neuronal synaptic plasticity / brain development / negative regulation of protein kinase activity / visual learning / wound healing / cerebral cortex development / cognition / osteoblast differentiation / positive regulation of GTPase activity / protein import into nucleus / Regulation of RAS by GAPs / positive regulation of neuron apoptotic process / MAPK cascade / presynapse / cellular response to heat / heart development / fibroblast proliferation / actin cytoskeleton organization / regulation of gene expression / angiogenesis
Similarity search - Function
Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain / CRAL-TRIO lipid binding domain profile. / Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) ...Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain / CRAL-TRIO lipid binding domain profile. / Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) / CRAL-TRIO lipid binding domain / CRAL-TRIO lipid binding domain superfamily / Rho GTPase activation protein / PH-like domain superfamily / Armadillo-type fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.25 Å
AuthorsLupton CJ / Bayly-Jones C / Ellisdon AM
Funding support Australia, 1 items
OrganizationGrant numberCountry
Not funded Australia
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1.
Authors: Christopher J Lupton / Charles Bayly-Jones / Laura D'Andrea / Cheng Huang / Ralf B Schittenhelm / Hari Venugopal / James C Whisstock / Michelle L Halls / Andrew M Ellisdon /
Abstract: Neurofibromin (NF1) mutations cause neurofibromatosis type 1 and drive numerous cancers, including breast and brain tumors. NF1 inhibits cellular proliferation through its guanosine triphosphatase- ...Neurofibromin (NF1) mutations cause neurofibromatosis type 1 and drive numerous cancers, including breast and brain tumors. NF1 inhibits cellular proliferation through its guanosine triphosphatase-activating protein (GAP) activity against rat sarcoma (RAS). In the present study, cryo-electron microscope studies reveal that the human ~640-kDa NF1 homodimer features a gigantic 30 × 10 nm array of α-helices that form a core lemniscate-shaped scaffold. Three-dimensional variability analysis captured the catalytic GAP-related domain and lipid-binding SEC-PH domains positioned against the core scaffold in a closed, autoinhibited conformation. We postulate that interaction with the plasma membrane may release the closed conformation to promote RAS inactivation. Our structural data further allow us to map the location of disease-associated NF1 variants and provide a long-sought-after structural explanation for the extreme susceptibility of the molecule to loss-of-function mutations. Collectively these findings present potential new routes for therapeutic modulation of the RAS pathway.
History
DepositionMay 4, 2021-
Header (metadata) releaseDec 15, 2021-
Map releaseDec 15, 2021-
UpdateMar 16, 2022-
Current statusMar 16, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.8
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  • Surface view colored by cylindrical radius
  • Surface level: 0.8
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  • Surface view with fitted model
  • Atomic models: PDB-7mp6
  • Surface level: 0.7
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7mp6
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23930.png

Downloads & links

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Map

FileDownload / File: emd_23930.map.gz / Format: CCP4 / Size: 38.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 2.388 Å
Density
Contour LevelBy AUTHOR: 0.3 / Movie #1: 0.8
Minimum - Maximum-0.87252855 - 2.3646345
Average (Standard dev.)0.0004042146 (±0.064507484)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions216216216
Spacing216216216
CellA=B=C: 515.808 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z2.3882.3882.388
M x/y/z216216216
origin x/y/z0.0000.0000.000
length x/y/z515.808515.808515.808
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ450450450
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS216216216
D min/max/mean-0.8732.3650.000

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Supplemental data

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Mask #1

Fileemd_23930_msk_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Additional map: #1

Fileemd_23930_additional_1.map
Projections & Slices
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Half map: #2

Fileemd_23930_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_23930_half_map_2.map
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Sample components

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Entire : Neurofibromin homodimer

EntireName: Neurofibromin homodimer
Components
  • Complex: Neurofibromin homodimer
    • Protein or peptide: Isoform I of Neurofibromin

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Supramolecule #1: Neurofibromin homodimer

SupramoleculeName: Neurofibromin homodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
Molecular weightExperimental: 630 KDa

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Macromolecule #1: Isoform I of Neurofibromin

MacromoleculeName: Isoform I of Neurofibromin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 318.407812 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDYKDDDDKA AHRPVEWVQA VVSRFDEQLP IKTGQQNTHT KVSTEHNKEC LINISKYKFS LVISGLTTIL KNVNNMRIFG EAAEKNLYL SQLIILDTLE KCLAGQPKDT MRLDETMLVK QLLPEICHFL HTCREGNQHA AELRNSASGV LFSLSCNNFN A VFSRISTR ...String:
MDYKDDDDKA AHRPVEWVQA VVSRFDEQLP IKTGQQNTHT KVSTEHNKEC LINISKYKFS LVISGLTTIL KNVNNMRIFG EAAEKNLYL SQLIILDTLE KCLAGQPKDT MRLDETMLVK QLLPEICHFL HTCREGNQHA AELRNSASGV LFSLSCNNFN A VFSRISTR LQELTVCSED NVDVHDIELL QYINVDCAKL KRLLKETAFK FKALKKVAQL AVINSLEKAF WNWVENYPDE FT KLYQIPQ TDMAECAEKL FDLVDGFAES TKRKAAVWPL QIILLILCPE IIQDISKDVV DENNMNKKLF LDSLRKALAG HGG SRQLTE SAAIACVKLC KASTYINWED NSVIFLLVQS MVVDLKNLLF NPSKPFSRGS QPADVDLMID CLVSCFRISP HNNQ HFKIC LAQNSPSTFH YVLVNSLHRI ITNSALDWWP KIDAVYCHSV ELRNMFGETL HKAVQGCGAH PAIRMAPSLT FKEKV TSLK FKEKPTDLET RSYKYLLLSM VKLIHADPKL LLCNPRKQGP ETQGSTAELI TGLVQLVPQS HMPEIAQEAM EALLVL HQL DSIDLWNPDA PVETFWEISS QMLFYICKKL TSHQMLSSTE ILKWLREILI CRNKFLLKNK QADRSSCHFL LFYGVGC DI PSSGNTSQMS MDHEELLRTP GASLRKGKGN SSMDSAAGCS GTPPICRQAQ TKLEVALYMF LWNPDTEAVL VAMSCFRH L CEEADIRCGV DEVSVHNLLP NYNTFMEFAS VSNMMSTGRA ALQKRVMALL RRIEHPTAGN TEAWEDTHAK WEQATKLIL NYPKAKMEDG QAAESLHKTI VKRRMSHVSG GGSIDLSDTD SLQEWINMTG FLCALGGVCL QQRSNSGLAT YSPPMGPVSE RKGSMISVM SSEGNADTPV SKFMDRLLSL MVCNHEKVGL QIRTNVKDLV GLELSPALYP MLFNKLKNTI SKFFDSQGQV L LTDTNTQF VEQTIAIMKN LLDNHTEGSS EHLGQASIET MMLNLVRYVR VLGNMVHAIQ IKTKLCQLVE VMMARRDDLS FC QEMKFRN KMVEYLTDWV MGTSNQAADD DVKCLTRDLD QASMEAVVSL LAGLPLQPEE GDGVELMEAK SQLFLKYFTL FMN LLNDCS EVEDESAQTG GRKRGMSRRL ASLRHCTVLA MSNLLNANVD SGLMHSIGLG YHKDLQTRAT FMEVLTKILQ QGTE FDTLA ETVLADRFER LVELVTMMGD QGELPIAMAL ANVVPCSQWD ELARVLVTLF DSRHLLYQLL WNMFSKEVEL ADSMQ TLFR GNSLASKIMT FCFKVYGATY LQKLLDPLLR IVITSSDWQH VSFEVDPTRL EPSESLEENQ RNLLQMTEKF FHAIIS SSS EFPPQLRSVC HCLYQVVSQR FPQNSIGAVG SAMFLRFINP AIVSPYEAGI LDKKPPPRIE RGLKLMSKIL QSIANHV LF TKEEHMRPFN DFVKSNFDAA RRFFLDIASD CPTSDAVNHS LSFISDGNVL ALHRLLWNNQ EKIGQYLSSN RDHKAVGR R PFDKMATLLA YLGPPEHKPV ADTHWSSLNL TSSKFEEFMT RHQVHEKEEF KALKTLSIFY QAGTSKAGNP IFYYVARRF KTGQINGDLL IYHVLLTLKP YYAKPYEIVV DLTHTGPSNR FKTDFLSKWF VVFPGFAYDN VSAVYIYNCN SWVREYTKYH ERLLTGLKG SKRLVFIDCP GKLAEHIEHE QQKLPAATLA LEEDLKVFHN ALKLAHKDTK VSIKVGSTAV QVTSAERTKV L GQSVFLND IYYASEIEEI CLVDENQFTL TIANQGTPLT FMHQECEAIV QSIIHIRTRW ELSQPDSIPQ HTKIRPKDVP GT LLNIALL NLGSSDPSLR SAAYNLLCAL TCTFNLKIEG QLLETSGLCI PANNTLFIVS ISKTLAANEP HLTLEFLEEC ISG FSKSSI ELKHLCLEYM TPWLSNLVRF CKHNDDAKRQ RVTAILDKLI TMTINEKQMY PSIQAKIWGS LGQITDLLDV VLDS FIKTS ATGGLGSIKA EVMADTAVAL ASGNVKLVSS KVIGRMCKII DKTCLSPTPT LEQHLMWDDI AILARYMLML SFNNS LDVA AHLPYLFHVV TFLVATGPLS LRASTHGLVI NIIHSLCTCS QLHFSEETKQ VLRLSLTEFS LPKFYLLFGI SKVKSA AVI AFRSSYRDRS FSPGSYERET FALTSLETVT EALLEIMEAC MRDIPTCKWL DQWTELAQRF AFQYNPSLQP RALVVFG CI SKRVSHGQIK QIIRILSKAL ESCLKGPDTY NSQVLIEATV IALTKLQPLL NKDSPLHKAL FWVAVAVLQL DEVNLYSA G TALLEQNLHT LDSLRIFNDK SPEEVFMAIR NPLEWHCKQM DHFVGLNFNS NFNFALVGHL LKGYRHPSPA IVARTVRIL HTLLTLVNKH RNCDKFEVNT QSVAYLAALL TVSEEVRSRC SLKHRKSLLL TDISMENVPM DTYPIHHGDP SYRTLKETQP WSSPKGSEG YLAATYPTVG QTSPRARKSM SLDMGQPSQA NTKKLLGTRK SFDHLISDTK APKRQEMESG ITTPPKMRRV A ETDYEMET QRISSSQQHP HLRKVSVSES NVLLDEEVLT DPKIQALLLT VLATLVKYTT DEFDQRILYE YLAEASVVFP KV FPVVHNL LDSKINTLLS LCQDPNLLNP IHGIVQSVVY HEESPPQYQT SYLQSFGFNG LWRFAGPFSK QTQIPDYAEL IVK FLDALI DTYLPGIDEE TSEESLLTPT SPYPPALQSQ LSITANLNLS NSMTSLATSQ HSPGIDKENV ELSPTTGHCN SGRT RHGSA SQVQKQRSAG SFKRNSIKKI V

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: Ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 6.25 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95564
FSC plot (resolution estimation)

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