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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


regulation of glial cell differentiation / forebrain astrocyte development / regulation of cell-matrix adhesion / negative regulation of neuroblast proliferation / metanephros development / negative regulation of oligodendrocyte differentiation / regulation of intracellular signal transduction / smooth muscle tissue development / regulation of blood vessel endothelial cell migration / camera-type eye morphogenesis ...regulation of glial cell differentiation / forebrain astrocyte development / regulation of cell-matrix adhesion / negative regulation of neuroblast proliferation / metanephros development / negative regulation of oligodendrocyte differentiation / regulation of intracellular signal transduction / smooth muscle tissue development / regulation of blood vessel endothelial cell migration / camera-type eye morphogenesis / forebrain morphogenesis / sympathetic nervous system development / cell communication / peripheral nervous system development / myelination in peripheral nervous system / phosphatidylcholine binding / collagen fibril organization / artery morphogenesis / phosphatidylethanolamine binding / pigmentation / adrenal gland development / regulation of bone resorption / regulation of postsynapse organization / spinal cord development / negative regulation of endothelial cell proliferation / regulation of angiogenesis / RAS signaling downstream of NF1 loss-of-function variants / positive regulation of GTPase activity / negative regulation of fibroblast proliferation / Schwann cell development / extracellular matrix organization / negative regulation of MAPK cascade / visual learning / liver development / negative regulation of cell migration / wound healing / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / brain development / cerebral cortex development / cognition / osteoblast differentiation / heart development / positive regulation of neuron apoptotic process / MAPK cascade / actin cytoskeleton organization / Regulation of RAS by GAPs / response to hypoxia / Ras protein signal transduction / positive regulation of apoptotic process / axon / nucleolus / dendrite / glutamatergic synapse / nucleoplasm / membrane / nucleus / plasma membrane / cytosol / cytoplasm
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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