+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23930 | |||||||||
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Title | Neurofibromin homodimer | |||||||||
Map data | ||||||||||
Sample |
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Keywords | tumor supressor / HEAT repeat / Ras-GAP / scaffold / ANTITUMOR PROTEIN | |||||||||
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 / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / gamma-aminobutyric acid secretion, neurotransmission / negative regulation of mast cell proliferation ...positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / gamma-aminobutyric acid secretion, neurotransmission / negative regulation of mast cell proliferation / mast cell apoptotic process / 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 / regulation of cell-matrix adhesion / forebrain morphogenesis / negative regulation of neurotransmitter secretion / hair follicle maturation / cell communication / regulation of blood vessel endothelial cell migration / smooth muscle tissue development / camera-type eye morphogenesis / negative regulation of oligodendrocyte differentiation / sympathetic nervous system development / peripheral nervous system development / myelination in peripheral nervous system / myeloid leukocyte migration / phosphatidylcholine binding / phosphatidylethanolamine binding / metanephros development / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of Ras protein signal transduction / collagen fibril organization / regulation of bone resorption / regulation of long-term synaptic potentiation / neural tube development / endothelial cell proliferation / forebrain astrocyte development / artery morphogenesis / regulation of postsynapse organization / regulation of synaptic transmission, GABAergic / negative regulation of neuroblast proliferation / adrenal gland development / negative regulation of protein import into nucleus / negative regulation of MAPK cascade / negative regulation of cell-matrix adhesion / pigmentation / regulation of GTPase activity / spinal cord development / Rac protein signal transduction / oligodendrocyte differentiation / negative regulation of osteoclast differentiation / negative regulation of endothelial cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of astrocyte differentiation / extrinsic apoptotic signaling pathway via death domain receptors / neuroblast proliferation / regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / Schwann cell development / negative regulation of angiogenesis / negative regulation of stem cell proliferation / negative regulation of fibroblast proliferation / extrinsic apoptotic signaling pathway in absence of ligand / skeletal muscle tissue development / negative regulation of MAP kinase activity / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / extracellular matrix organization / osteoclast differentiation / positive regulation of GTPase activity / liver development / negative regulation of cell migration / stem cell proliferation / long-term synaptic potentiation / negative regulation of protein kinase activity / regulation of long-term neuronal synaptic plasticity / wound healing / visual learning / brain development / cognition / cerebral cortex development / Regulation of RAS by GAPs / osteoblast differentiation / protein import into nucleus / positive regulation of neuron apoptotic process / MAPK cascade / presynapse / regulation of gene expression / heart development / cellular response to heat / fibroblast proliferation / actin cytoskeleton organization Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 6.25 Å | |||||||||
Authors | Lupton CJ / Bayly-Jones C | |||||||||
Funding support | Australia, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23930.map.gz | 19.4 MB | EMDB map data format | |
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Header (meta data) | emd-23930-v30.xml emd-23930.xml | 18.5 KB 18.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23930_fsc.xml | 7.9 KB | Display | FSC data file |
Images | emd_23930.png | 43.9 KB | ||
Masks | emd_23930_msk_1.map | 38.4 MB | Mask map | |
Filedesc metadata | emd-23930.cif.gz | 7 KB | ||
Others | emd_23930_additional_1.map.gz emd_23930_half_map_1.map.gz emd_23930_half_map_2.map.gz | 36.3 MB 35.6 MB 35.6 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23930 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23930 | HTTPS FTP |
-Validation report
Summary document | emd_23930_validation.pdf.gz | 762.3 KB | Display | EMDB validaton report |
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Full document | emd_23930_full_validation.pdf.gz | 761.9 KB | Display | |
Data in XML | emd_23930_validation.xml.gz | 14.5 KB | Display | |
Data in CIF | emd_23930_validation.cif.gz | 18.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23930 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23930 | HTTPS FTP |
-Related structure data
Related structure data | 7mp6MC 7mocC 7mp5C C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23930.map.gz / Format: CCP4 / Size: 38.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 2.388 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_23930_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: #1
File | emd_23930_additional_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_23930_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_23930_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Neurofibromin homodimer
Entire | Name: Neurofibromin homodimer |
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Components |
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-Supramolecule #1: Neurofibromin homodimer
Supramolecule | Name: Neurofibromin homodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 630 KDa |
-Macromolecule #1: Isoform I of Neurofibromin
Macromolecule | Name: Isoform I of Neurofibromin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 318.407812 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 UniProtKB: Neurofibromin |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |