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- PDB-7pgq: GAP-SecPH region of human neurofibromin isoform 2 in closed confo... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7pgq | ||||||||||||
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Title | GAP-SecPH region of human neurofibromin isoform 2 in closed conformation. | ||||||||||||
![]() | Neurofibromin | ||||||||||||
![]() | SIGNALING PROTEIN / Neurofibromin / Cancer / GAP / Ras / Neurofibromatosis type 1 | ||||||||||||
Function / homology | ![]() positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / gamma-aminobutyric acid secretion, neurotransmission / 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 / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / gamma-aminobutyric acid secretion, neurotransmission / negative regulation of mast cell proliferation / mast cell apoptotic process / 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 / negative regulation of neurotransmitter secretion / forebrain morphogenesis / hair follicle maturation / cell communication / regulation of blood vessel endothelial cell migration / smooth muscle tissue development / camera-type eye morphogenesis / negative regulation of oligodendrocyte differentiation / sympathetic nervous system development / myelination in peripheral nervous system / myeloid leukocyte migration / peripheral nervous system development / phosphatidylcholine binding / 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 / artery morphogenesis / regulation of postsynapse organization / regulation of synaptic transmission, GABAergic / negative regulation of neuroblast proliferation / adrenal gland development / negative regulation of protein import into nucleus / negative regulation of MAPK cascade / negative regulation of cell-matrix adhesion / pigmentation / 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 / extrinsic apoptotic signaling pathway in absence of ligand / skeletal muscle tissue development / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / negative regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / extracellular matrix organization / osteoclast differentiation / positive regulation of GTPase activity / liver development / negative regulation of cell migration / negative regulation of MAP kinase activity / stem cell proliferation / long-term synaptic potentiation / negative regulation of protein kinase activity / regulation of long-term neuronal synaptic plasticity / wound healing / visual learning / brain development / cognition / cerebral cortex development / Regulation of RAS by GAPs / osteoblast differentiation / protein import into nucleus / positive regulation of neuron apoptotic process / MAPK cascade / presynapse / heart development / cellular response to heat / fibroblast proliferation / actin cytoskeleton organization / regulation of gene expression Similarity search - Function | ||||||||||||
Biological species | ![]() | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å | ||||||||||||
![]() | Naschberger, A. / Baradaran, R. / Carroni, M. / Rupp, B. | ||||||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 716.2 KB | Display | ![]() |
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PDB format | ![]() | 557.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 13392MC ![]() 7pgpC ![]() 7pgrC ![]() 7pgsC ![]() 7pgtC ![]() 7pguC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 319757.656 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Chemical | ChemComp-PEV / ( | #3: Chemical | ChemComp-ZN / | Has ligand of interest | N | |
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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 |
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Sample preparation
Component | Name: Homo-dimer of human Neurofibromin Isoform 2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 640 kDa/nm / Experimental value: YES |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2100 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 1 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 100684 / Symmetry type: POINT |