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- PDB-7pgr: The structure of human neurofibromin isoform 2 in closed conformation -

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Basic information

Entry
Database: PDB / ID: 7pgr
TitleThe structure of human neurofibromin isoform 2 in closed conformation
ComponentsNeurofibromin
KeywordsSIGNALING PROTEIN / Neurofibromin / Cancer / GAP / Ras / Neurofibromatosis type 1
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 / forebrain morphogenesis / regulation of cell-matrix adhesion / negative regulation of neurotransmitter secretion / 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 / myelination in peripheral nervous system / sympathetic nervous system development / phosphatidylcholine binding / myeloid leukocyte migration / phosphatidylethanolamine binding / peripheral nervous system development / metanephros development / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / endothelial cell proliferation / artery morphogenesis / collagen fibril organization / regulation of bone resorption / regulation of long-term synaptic potentiation / neural tube development / regulation of postsynapse organization / forebrain astrocyte development / pigmentation / negative regulation of neuroblast proliferation / regulation of synaptic transmission, GABAergic / adrenal gland development / negative regulation of protein import into nucleus / negative regulation of cell-matrix adhesion / spinal cord development / regulation of GTPase activity / negative regulation of endothelial cell proliferation / negative regulation of MAPK cascade / Rac protein signal transduction / oligodendrocyte differentiation / negative regulation of osteoclast differentiation / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of astrocyte differentiation / neuroblast proliferation / extrinsic apoptotic signaling pathway via death domain receptors / regulation of angiogenesis / Schwann cell development / skeletal muscle tissue development / negative regulation of fibroblast proliferation / negative regulation of stem cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / GTPase activator activity / extracellular matrix organization / negative regulation of angiogenesis / osteoclast differentiation / regulation of ERK1 and ERK2 cascade / negative regulation of MAP kinase activity / negative regulation of cell migration / liver development / phosphatidylinositol 3-kinase/protein kinase B signal transduction / long-term synaptic potentiation / stem cell proliferation / regulation of long-term neuronal synaptic plasticity / brain development / negative regulation of protein kinase activity / visual learning / wound healing / cerebral cortex development / cognition / osteoblast differentiation / positive regulation of GTPase activity / protein import into nucleus / Regulation of RAS by GAPs / positive regulation of neuron apoptotic process / MAPK cascade / presynapse / cellular response to heat / heart development / fibroblast proliferation / actin cytoskeleton organization / regulation of gene expression / angiogenesis
Similarity search - Function
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) ...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: 4 Å
AuthorsNaschberger, A. / Baradaran, R. / Carroni, M. / Rupp, B.
Funding support Austria, 3items
OrganizationGrant numberCountry
Knut and Alice Wallenberg Foundation431042 Austria
Austrian Science FundP28395 Austria
Austrian Science FundI5152 Austria
CitationJournal: Nature / Year: 2021
Title: The structure of neurofibromin isoform 2 reveals different functional states.
Authors: Andreas Naschberger / Rozbeh Baradaran / Bernhard Rupp / Marta Carroni /
Abstract: The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to ...The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to dysfunction in the protein neurofibromin (Nf1). As a GTPase-activating protein, a key function of Nf1 is repression of the Ras oncogene signalling cascade. We determined the human Nf1 dimer structure at an overall resolution of 3.3 Å. The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing isoform 2 in a closed, self-inhibited, Zn-stabilized state and an open state. In the closed conformation, HEAT/ARM core domains shield the GTPase-activating protein-related domain (GRD) so that Ras binding is sterically inhibited. In a distinctly different, open conformation of one protomer, a large-scale movement of the GRD occurs, which is necessary to access Ras, whereas Sec14-PH reorients to allow interaction with the cellular membrane. Zn incubation of Nf1 leads to reduced Ras-GAP activity with both protomers in the self-inhibited, closed conformation stabilized by a Zn binding site between the N-HEAT/ARM domain and the GRD-Sec14-PH linker. The transition between closed, self-inhibited states of Nf1 and open states provides guidance for targeted studies deciphering the complex molecular mechanism behind the widespread neurofibromatosis syndrome and Nf1 dysfunction in carcinogenesis.
History
DepositionAug 15, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 17, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 24, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
N: Neurofibromin
F: Neurofibromin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)639,6464
Polymers639,5152
Non-polymers1312
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10530 Å2
ΔGint-146 kcal/mol
Surface area223430 Å2

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Components

#1: Protein Neurofibromin / / Neurofibromatosis-related protein NF-1


Mass: 319757.656 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
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: Homo-dimer of human Neurofibromin Isoform 2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.64 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 130329 / Symmetry type: POINT

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