+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-13394 | ||||||||||||
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Title | Consensus structure of human Neurofibromin isoform 2 | ||||||||||||
Map data | |||||||||||||
Sample |
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Keywords | Neurofibromin / Cancer / GAP / Ras / Neurofibromatosis type 1 / SIGNALING 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 / myelination in peripheral nervous system / myeloid leukocyte migration / peripheral nervous system development / phosphatidylcholine binding / metanephros development / phosphatidylethanolamine binding / 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 / negative regulation of MAPK cascade / adrenal gland development / negative regulation of protein import into nucleus / pigmentation / negative regulation of cell-matrix adhesion / spinal cord development / regulation of GTPase activity / 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 / Schwann cell development / negative regulation of stem cell proliferation / negative regulation of fibroblast proliferation / skeletal muscle tissue development / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / extracellular matrix organization / negative regulation of angiogenesis / negative regulation of cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / regulation of ERK1 and ERK2 cascade / osteoclast differentiation / positive regulation of GTPase activity / liver development / negative regulation of MAP kinase activity / stem cell proliferation / long-term synaptic potentiation / regulation of long-term neuronal synaptic plasticity / negative regulation of protein kinase activity / wound healing / visual learning / brain development / cerebral cortex development / cognition / Regulation of RAS by GAPs / osteoblast differentiation / protein import into nucleus / MAPK cascade / positive regulation of neuron apoptotic process / presynapse / heart development / cellular response to heat / fibroblast proliferation / actin cytoskeleton organization / regulation of gene expression Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | ||||||||||||
Authors | Naschberger A / Baradaran R | ||||||||||||
Funding support | Austria, 3 items
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Citation | Journal: Nature / Year: 2021 Title: The structure of neurofibromin isoform 2 reveals different functional states. Authors: Andreas Naschberger / Rozbeh Baradaran / Bernhard Rupp / Marta Carroni / Abstract: The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to ...The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to dysfunction in the protein neurofibromin (Nf1). As a GTPase-activating protein, a key function of Nf1 is repression of the Ras oncogene signalling cascade. We determined the human Nf1 dimer structure at an overall resolution of 3.3 Å. The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing isoform 2 in a closed, self-inhibited, Zn-stabilized state and an open state. In the closed conformation, HEAT/ARM core domains shield the GTPase-activating protein-related domain (GRD) so that Ras binding is sterically inhibited. In a distinctly different, open conformation of one protomer, a large-scale movement of the GRD occurs, which is necessary to access Ras, whereas Sec14-PH reorients to allow interaction with the cellular membrane. Zn incubation of Nf1 leads to reduced Ras-GAP activity with both protomers in the self-inhibited, closed conformation stabilized by a Zn binding site between the N-HEAT/ARM domain and the GRD-Sec14-PH linker. The transition between closed, self-inhibited states of Nf1 and open states provides guidance for targeted studies deciphering the complex molecular mechanism behind the widespread neurofibromatosis syndrome and Nf1 dysfunction in carcinogenesis. | ||||||||||||
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_13394.map.gz | 214.2 MB | EMDB map data format | |
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Header (meta data) | emd-13394-v30.xml emd-13394.xml | 18.4 KB 18.4 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_13394_fsc.xml | 16.5 KB | Display | FSC data file |
Images | emd_13394.png | 61.1 KB | ||
Masks | emd_13394_msk_1.map | 396.1 MB | Mask map | |
Filedesc metadata | emd-13394.cif.gz | 6.9 KB | ||
Others | emd_13394_additional_1.map.gz emd_13394_half_map_1.map.gz emd_13394_half_map_2.map.gz | 353.8 MB 319.8 MB 319.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-13394 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13394 | HTTPS FTP |
-Validation report
Summary document | emd_13394_validation.pdf.gz | 662.3 KB | Display | EMDB validaton report |
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Full document | emd_13394_full_validation.pdf.gz | 661.8 KB | Display | |
Data in XML | emd_13394_validation.xml.gz | 24.1 KB | Display | |
Data in CIF | emd_13394_validation.cif.gz | 32.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13394 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13394 | HTTPS FTP |
-Related structure data
Related structure data | 7pgsMC 7pgpC 7pgqC 7pgrC 7pgtC 7pguC M: atomic model generated by this map C: citing same article (ref.) |
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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_13394.map.gz / Format: CCP4 / Size: 396.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.4638 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_13394_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: #1
File | emd_13394_additional_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_13394_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_13394_half_map_2.map | ||||||||||||
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Density Histograms |
-Sample components
-Entire : Homo-dimer of human Neurofibromin Isoform 2
Entire | Name: Homo-dimer of human Neurofibromin Isoform 2 |
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Components |
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-Supramolecule #1: Homo-dimer of human Neurofibromin Isoform 2
Supramolecule | Name: Homo-dimer of human Neurofibromin Isoform 2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 640 KDa |
-Macromolecule #1: Neurofibromin
Macromolecule | Name: 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: 319.757656 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MAAHRPVEWV QAVVSRFDEQ LPIKTGQQNT HTKVSTEHNK ECLINISKYK FSLVISGLTT ILKNVNNMRI FGEAAEKNLY LSQLIILDT LEKCLAGQPK DTMRLDETML VKQLLPEICH FLHTCREGNQ HAAELRNSAS GVLFSLSCNN FNAVFSRIST R LQELTVCS ...String: MAAHRPVEWV QAVVSRFDEQ LPIKTGQQNT HTKVSTEHNK ECLINISKYK FSLVISGLTT ILKNVNNMRI FGEAAEKNLY LSQLIILDT LEKCLAGQPK DTMRLDETML VKQLLPEICH FLHTCREGNQ HAAELRNSAS GVLFSLSCNN FNAVFSRIST R LQELTVCS EDNVDVHDIE LLQYINVDCA KLKRLLKETA FKFKALKKVA QLAVINSLEK AFWNWVENYP DEFTKLYQIP QT DMAECAE KLFDLVDGFA ESTKRKAAVW PLQIILLILC PEIIQDISKD VVDENNMNKK LFLDSLRKAL AGHGGSRQLT ESA AIACVK LCKASTYINW EDNSVIFLLV QSMVVDLKNL LFNPSKPFSR GSQPADVDLM IDCLVSCFRI SPHNNQHFKI CLAQ NSPST FHYVLVNSLH RIITNSALDW WPKIDAVYCH SVELRNMFGE TLHKAVQGCG AHPAIRMAPS LTFKEKVTSL KFKEK PTDL ETRSYKYLLL SMVKLIHADP KLLLCNPRKQ GPETQGSTAE LITGLVQLVP QSHMPEIAQE AMEALLVLHQ LDSIDL WNP DAPVETFWEI SSQMLFYICK KLTSHQMLSS TEILKWLREI LICRNKFLLK NKQADRSSCH FLLFYGVGCD IPSSGNT SQ MSMDHEELLR TPGASLRKGK GNSSMDSAAG CSGTPPICRQ AQTKLEVALY MFLWNPDTEA VLVAMSCFRH LCEEADIR C GVDEVSVHNL LPNYNTFMEF ASVSNMMSTG RAALQKRVMA LLRRIEHPTA GNTEAWEDTH AKWEQATKLI LNYPKAKME DGQAAESLHK TIVKRRMSHV SGGGSIDLSD TDSLQEWINM TGFLCALGGV CLQQRSNSGL ATYSPPMGPV SERKGSMISV MSSEGNADT PVSKFMDRLL SLMVCNHEKV GLQIRTNVKD LVGLELSPAL YPMLFNKLKN TISKFFDSQG QVLLTDTNTQ F VEQTIAIM KNLLDNHTEG SSEHLGQASI ETMMLNLVRY VRVLGNMVHA IQIKTKLCQL VEVMMARRDD LSFCQEMKFR NK MVEYLTD WVMGTSNQAA DDDVKCLTRD LDQASMEAVV SLLAGLPLQP EEGDGVELME AKSQLFLKYF TLFMNLLNDC SEV EDESAQ TGGRKRGMSR RLASLRHCTV LAMSNLLNAN VDSGLMHSIG LGYHKDLQTR ATFMEVLTKI LQQGTEFDTL AETV LADRF ERLVELVTMM GDQGELPIAM ALANVVPCSQ WDELARVLVT LFDSRHLLYQ LLWNMFSKEV ELADSMQTLF RGNSL ASKI MTFCFKVYGA TYLQKLLDPL LRIVITSSDW QHVSFEVDPT RLEPSESLEE NQRNLLQMTE KFFHAIISSS SEFPPQ LRS VCHCLYQATC HSLLNKATVK EKKENKKSVV SQRFPQNSIG AVGSAMFLRF INPAIVSPYE AGILDKKPPP RIERGLK LM SKILQSIANH VLFTKEEHMR PFNDFVKSNF DAARRFFLDI ASDCPTSDAV NHSLSFISDG NVLALHRLLW NNQEKIGQ Y LSSNRDHKAV GRRPFDKMAT LLAYLGPPEH KPVADTHWSS LNLTSSKFEE FMTRHQVHEK EEFKALKTLS IFYQAGTSK AGNPIFYYVA RRFKTGQING DLLIYHVLLT LKPYYAKPYE IVVDLTHTGP SNRFKTDFLS KWFVVFPGFA YDNVSAVYIY NCNSWVREY TKYHERLLTG LKGSKRLVFI DCPGKLAEHI EHEQQKLPAA TLALEEDLKV FHNALKLAHK DTKVSIKVGS T AVQVTSAE RTKVLGQSVF LNDIYYASEI EEICLVDENQ FTLTIANQGT PLTFMHQECE AIVQSIIHIR TRWELSQPDS IP QHTKIRP KDVPGTLLNI ALLNLGSSDP SLRSAAYNLL CALTCTFNLK IEGQLLETSG LCIPANNTLF IVSISKTLAA NEP HLTLEF LEECISGFSK SSIELKHLCL EYMTPWLSNL VRFCKHNDDA KRQRVTAILD KLITMTINEK QMYPSIQAKI WGSL GQITD LLDVVLDSFI KTSATGGLGS IKAEVMADTA VALASGNVKL VSSKVIGRMC KIIDKTCLSP TPTLEQHLMW DDIAI LARY MLMLSFNNSL DVAAHLPYLF HVVTFLVATG PLSLRASTHG LVINIIHSLC TCSQLHFSEE TKQVLRLSLT EFSLPK FYL LFGISKVKSA AVIAFRSSYR DRSFSPGSYE RETFALTSLE TVTEALLEIM EACMRDIPTC KWLDQWTELA QRFAFQY NP SLQPRALVVF GCISKRVSHG QIKQIIRILS KALESCLKGP DTYNSQVLIE ATVIALTKLQ PLLNKDSPLH KALFWVAV A VLQLDEVNLY SAGTALLEQN LHTLDSLRIF NDKSPEEVFM AIRNPLEWHC KQMDHFVGLN FNSNFNFALV GHLLKGYRH PSPAIVARTV RILHTLLTLV NKHRNCDKFE VNTQSVAYLA ALLTVSEEVR SRCSLKHRKS LLLTDISMEN VPMDTYPIHH GDPSYRTLK ETQPWSSPKG SEGYLAATYP TVGQTSPRAR KSMSLDMGQP SQANTKKLLG TRKSFDHLIS DTKAPKRQEM E SGITTPPK MRRVAETDYE METQRISSSQ QHPHLRKVSV SESNVLLDEE VLTDPKIQAL LLTVLATLVK YTTDEFDQRI LY EYLAEAS VVFPKVFPVV HNLLDSKINT LLSLCQDPNL LNPIHGIVQS VVYHEESPPQ YQTSYLQSFG FNGLWRFAGP FSK QTQIPD YAELIVKFLD ALIDTYLPGI DEETSEESLL TPTSPYPPAL QSQLSITANL NLSNSMTSLA TSQHSPGIDK ENVE LSPTT GHCNSGRTRH GSASQVQKQR SAGSFKRNSI KKIV UniProtKB: Neurofibromin |
-Macromolecule #2: ZINC ION
Macromolecule | Name: ZINC ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: ZN |
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Molecular weight | Theoretical: 65.409 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |