+Open data
-Basic information
Entry | Database: PDB / ID: 7mp5 | ||||||
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Title | Autoinhibited neurofibrobmin | ||||||
Components | Isoform I of Neurofibromin | ||||||
Keywords | ANTITUMOR PROTEIN / scaffold / RAS-GAP / HEAT repeat / autoinhibition / tumour suppressor | ||||||
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 / regulation of cell-matrix adhesion / forebrain morphogenesis / negative regulation of neurotransmitter secretion / hair follicle maturation / cell communication / regulation of blood vessel endothelial cell migration / camera-type eye morphogenesis / smooth muscle tissue development / negative regulation of oligodendrocyte differentiation / sympathetic nervous system development / myelination in peripheral nervous system / myeloid leukocyte migration / phosphatidylcholine binding / peripheral nervous system development / 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 / pigmentation / 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 / 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 / GTPase activator activity / negative regulation of cell migration / osteoclast differentiation / regulation of ERK1 and ERK2 cascade / phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / brain development / visual learning / cerebral cortex development / cognition / positive regulation of GTPase activity / osteoblast differentiation / Regulation of RAS by GAPs / 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 | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.6 Å | ||||||
Authors | Lupton, C.J. / Bayly-Jones, C. / Ellisdon, A.M. | ||||||
Funding support | Australia, 1items
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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 | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7mp5.cif.gz | 477.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7mp5.ent.gz | 348.6 KB | Display | PDB format |
PDBx/mmJSON format | 7mp5.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/mp/7mp5 ftp://data.pdbj.org/pub/pdb/validation_reports/mp/7mp5 | HTTPS FTP |
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-Related structure data
Related structure data | 23929MC 7mocC 7mp6C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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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.) Homo sapiens (human) / Gene: NF1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21359 |
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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 |
-Sample preparation
Component | Name: Neurofibromin / Type: COMPLEX / Details: Autoinhibited state of neurofibromin / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 0.636 MDa / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
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 | Cryogen name: ETHANE |
-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: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm |
Image recording | Electron dose: 40 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 5.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 9238 / Symmetry type: POINT |