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Open data
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Basic information
Entry | Database: PDB / ID: 7moc | ||||||
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Title | Neurofibromin core | ||||||
![]() | Isoform I of Neurofibromin | ||||||
![]() | ANTITUMOR PROTEIN / Scaffold / RAS-GAP / HEAT repeat / Autoinhibition | ||||||
Function / homology | ![]() 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 / 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 / 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 / negative regulation of angiogenesis / negative regulation of cell migration / extracellular matrix organization / phosphatidylinositol 3-kinase/protein kinase B signal transduction / osteoclast differentiation / GTPase activator activity / regulation of ERK1 and ERK2 cascade / 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 | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.56 Å | ||||||
![]() | Lupton, C.J. / Bayly-Jones, C. / Ellisdon, A.M. | ||||||
Funding support | 1items
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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
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 380.6 KB | Display | ![]() |
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PDB format | ![]() | 264.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.3 MB | Display | ![]() |
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Full document | ![]() | 1.3 MB | Display | |
Data in XML | ![]() | 55.6 KB | Display | |
Data in CIF | ![]() | 85.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 23924MC ![]() 7mp5C ![]() 7mp6C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 318407.812 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Neurofibromin / Type: COMPLEX / Details: A single lobe of the neurofibromin dimer / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 0.636 MDa / Experimental value: YES |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 8 |
Specimen | Conc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Alignment procedure: COMA FREE |
Image recording | Electron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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Symmetry | Point symmetry: C1 (asymmetric) |
3D reconstruction | Resolution: 4.56 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 34933 / Symmetry type: POINT |