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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-23929 | |||||||||
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Title | Autoinhibited neurofibrobmin | |||||||||
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Function / homology | ![]() positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / gamma-aminobutyric acid secretion, neurotransmission / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Lupton CJ / Bayly-Jones C | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 31.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.9 KB 18.9 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.5 KB | Display | ![]() |
Images | ![]() | 59.5 KB | ||
Masks | ![]() | 64 MB | ![]() | |
Filedesc metadata | ![]() | 7.1 KB | ||
Others | ![]() ![]() ![]() | 32.8 MB 59.4 MB 59.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7mp5MC ![]() 7mocC ![]() 7mp6C C: citing same article ( M: atomic model generated by this map |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.194 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
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-Additional map: Sharpened map
File | emd_23929_additional_1.map | ||||||||||||
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Annotation | Sharpened map | ||||||||||||
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-Half map: #1
File | emd_23929_half_map_1.map | ||||||||||||
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-Half map: #2
File | emd_23929_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Neurofibromin
Entire | Name: Neurofibromin![]() |
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Components |
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-Supramolecule #1: Neurofibromin
Supramolecule | Name: Neurofibromin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: Autoinhibited state of neurofibromin |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 636 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: ![]() ![]() |
Molecular weight | Theoretical: 318.407812 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
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: ![]() |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 0.4 mg/mL |
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Buffer | pH: 8 |
Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 40.0 e/Å2 |
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |