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- PDB-7mp6: Neurofibromin homodimer -

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Basic information

Entry
Database: PDB / ID: 7mp6
TitleNeurofibromin homodimer
ComponentsIsoform I of Neurofibromin
KeywordsANTITUMOR PROTEIN / tumor supressor / HEAT repeat / Ras-GAP / scaffold
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 / Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / Schwann cell proliferation / 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 / Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / Schwann cell proliferation / negative regulation of mast cell proliferation / mast cell apoptotic process / gamma-aminobutyric acid secretion, neurotransmission / vascular associated smooth muscle cell proliferation / glutamate secretion, neurotransmission / negative regulation of Schwann cell proliferation / mast 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 / sympathetic nervous system development / myeloid leukocyte migration / peripheral nervous system development / myelination in peripheral nervous system / phosphatidylcholine binding / negative regulation of Ras protein signal transduction / metanephros development / phosphatidylethanolamine binding / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / collagen fibril organization / regulation of long-term synaptic potentiation / endothelial cell proliferation / regulation of postsynapse organization / regulation of bone resorption / neural tube development / artery morphogenesis / forebrain astrocyte development / adrenal gland development / negative regulation of neuroblast proliferation / negative regulation of protein import into nucleus / pigmentation / spinal cord development / regulation of synaptic transmission, GABAergic / negative regulation of astrocyte differentiation / negative regulation of vascular associated smooth muscle cell migration / negative regulation of endothelial cell proliferation / Rac protein signal transduction / negative regulation of osteoclast differentiation / oligodendrocyte differentiation / RAS signaling downstream of NF1 loss-of-function variants / extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of cell-matrix adhesion / neuroblast proliferation / regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / Schwann cell development / skeletal muscle tissue development / negative regulation of stem cell proliferation / negative regulation of MAPK cascade / negative regulation of fibroblast proliferation / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of endothelial cell proliferation / positive regulation of GTPase activity / extracellular matrix organization / GTPase activator activity / osteoclast differentiation / negative regulation of angiogenesis / negative regulation of cell migration / stem cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / liver development / regulation of long-term neuronal synaptic plasticity / cerebral cortex development / brain development / visual learning / Regulation of RAS by GAPs / cognition / long-term synaptic potentiation / protein import into nucleus / osteoblast differentiation / MAPK cascade / positive regulation of neuron apoptotic process / presynapse / regulation of gene expression / cellular response to heat / heart development / actin cytoskeleton organization / fibroblast proliferation / angiogenesis / neuron apoptotic process / 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 (rasGAP) domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins (rasGAP) domain 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 (rasGAP) domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins (rasGAP) domain 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: 6.25 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
  • Evidence: cross-linking, Crosslinking mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area9130 Å2
ΔGint-75 kcal/mol
Surface area132270 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 homodimer / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.63 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 6.25 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95564 / Symmetry type: POINT

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