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- PDB-7mp5: Autoinhibited neurofibrobmin -

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Basic information

Entry
Database: PDB / ID: 7mp5
TitleAutoinhibited neurofibrobmin
ComponentsIsoform I of Neurofibromin
KeywordsANTITUMOR 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 / observational learning / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / Schwann cell proliferation / Schwann cell migration / 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 / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / Schwann cell proliferation / Schwann cell migration / negative regulation of mast cell proliferation / mast cell apoptotic process / gamma-aminobutyric acid secretion, neurotransmission / 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 neurotransmitter secretion / forebrain morphogenesis / regulation of cell-matrix adhesion / hair follicle maturation / regulation of blood vessel endothelial cell migration / cell communication / camera-type eye morphogenesis / smooth muscle tissue development / negative regulation of oligodendrocyte differentiation / myeloid leukocyte migration / sympathetic nervous system development / peripheral nervous system development / myelination in peripheral nervous system / phosphatidylcholine binding / metanephros development / negative regulation of Ras protein signal transduction / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / phosphatidylethanolamine binding / collagen fibril organization / endothelial cell proliferation / regulation of long-term synaptic potentiation / regulation of bone resorption / regulation of postsynapse organization / neural tube development / artery morphogenesis / forebrain astrocyte development / negative regulation of neuroblast proliferation / adrenal gland development / negative regulation of protein import into nucleus / pigmentation / regulation of synaptic transmission, GABAergic / spinal cord development / Rac protein signal transduction / negative regulation of vascular associated smooth muscle cell migration / negative regulation of endothelial cell proliferation / negative regulation of osteoclast differentiation / oligodendrocyte differentiation / negative regulation of astrocyte differentiation / RAS signaling downstream of NF1 loss-of-function variants / extrinsic apoptotic signaling pathway via death domain receptors / neuroblast proliferation / negative regulation of cell-matrix adhesion / regulation of angiogenesis / negative regulation of MAPK cascade / Schwann cell development / regulation of ERK1 and ERK2 cascade / negative regulation of stem cell proliferation / skeletal muscle tissue development / negative regulation of fibroblast proliferation / 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 / positive regulation of GTPase activity / osteoclast differentiation / GTPase activator activity / negative regulation of angiogenesis / negative regulation of cell migration / liver development / stem cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of long-term neuronal synaptic plasticity / wound healing / brain development / visual learning / cerebral cortex development / long-term synaptic potentiation / cognition / protein import into nucleus / Regulation of RAS by GAPs / osteoblast differentiation / positive regulation of neuron apoptotic process / MAPK cascade / presynapse / cellular response to heat / heart development / actin cytoskeleton organization / regulation of gene expression / fibroblast proliferation / neuron apoptotic process / angiogenesis / Ras protein signal transduction / response to hypoxia
Similarity search - Function
: / PH domain-like / Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain ...: / PH domain-like / Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain / CRAL-TRIO lipid binding domain profile. / Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) / CRAL-TRIO lipid binding domain / CRAL-TRIO lipid binding domain superfamily / Rho GTPase activation protein / PH-like domain superfamily / Armadillo-type fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.6 Å
AuthorsLupton, C.J. / Bayly-Jones, C. / Ellisdon, A.M.
Funding support Australia, 1items
OrganizationGrant numberCountry
Not funded Australia
CitationJournal: 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
DepositionMay 4, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 15, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 29, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 16, 2022Group: Structure summary / Category: audit_author
Revision 1.3May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
A: Isoform I of Neurofibromin
B: Isoform I of Neurofibromin


Theoretical massNumber of molelcules
Total (without water)636,8162
Polymers636,8162
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6320 Å2
ΔGint-46 kcal/mol
Surface area100420 Å2

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Components

#1: Protein Isoform I of Neurofibromin / Neurofibromatosis-related protein NF-1


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

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Neurofibromin / Type: COMPLEX / Details: Autoinhibited state of neurofibromin / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.636 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 5.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 9238 / Symmetry type: POINT

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