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- EMDB-13396: Autoinhibited structure of human neurofibromin isoform 2 stabiliz... -

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Basic information

Entry
Database: EMDB / ID: EMD-13396
TitleAutoinhibited structure of human neurofibromin isoform 2 stabilized by Zinc.
Map dataComposite map generated from core-, GAP-SecPH- and tip-maps.
Sample
  • Complex: Homo-dimer of human Neurofibromin Isoform 2
    • Protein or peptide: Neurofibromin
  • Ligand: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
  • Ligand: ZINC ION
  • Ligand: water
KeywordsNeurofibromin / Cancer / GAP / Ras / Neurofibromatosis type 1 / SIGNALING PROTEIN
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 / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / negative regulation of mast cell proliferation / gamma-aminobutyric acid secretion, neurotransmission ...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 / negative regulation of mast cell proliferation / gamma-aminobutyric acid secretion, neurotransmission / 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 neurotransmitter secretion / negative regulation of vascular associated smooth muscle cell migration / positive regulation of adenylate cyclase activity / forebrain morphogenesis / hair follicle maturation / regulation of cell-matrix adhesion / regulation of blood vessel endothelial cell migration / smooth muscle tissue development / camera-type eye morphogenesis / cell communication / negative regulation of oligodendrocyte differentiation / peripheral nervous system development / sympathetic nervous system development / myeloid leukocyte migration / myelination in peripheral nervous system / phosphatidylcholine binding / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / metanephros development / negative regulation of Ras protein signal transduction / phosphatidylethanolamine binding / regulation of bone resorption / collagen fibril organization / regulation of long-term synaptic potentiation / neural tube development / endothelial cell proliferation / forebrain astrocyte development / artery morphogenesis / pigmentation / regulation of postsynapse organization / negative regulation of neuroblast proliferation / negative regulation of protein import into nucleus / regulation of synaptic transmission, GABAergic / adrenal gland development / negative regulation of cell-matrix adhesion / regulation of GTPase activity / spinal cord development / Rac protein signal transduction / negative regulation of osteoclast differentiation / negative regulation of endothelial cell proliferation / oligodendrocyte differentiation / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of astrocyte differentiation / extrinsic apoptotic signaling pathway via death domain receptors / neuroblast proliferation / negative regulation of MAPK cascade / regulation of angiogenesis / Schwann cell development / negative regulation of stem cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of fibroblast proliferation / negative regulation of MAP kinase activity / positive regulation of vascular associated smooth muscle cell proliferation / skeletal muscle tissue development / positive regulation of endothelial cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of ERK1 and ERK2 cascade / GTPase activator activity / extracellular matrix organization / negative regulation of angiogenesis / osteoclast differentiation / liver development / positive regulation of GTPase activity / negative regulation of cell migration / stem cell proliferation / long-term synaptic potentiation / negative regulation of protein kinase activity / wound healing / regulation of long-term neuronal synaptic plasticity / brain development / visual learning / cerebral cortex development / cognition / osteoblast differentiation / Regulation of RAS by GAPs / protein import into nucleus / positive regulation of neuron apoptotic process / MAPK cascade / heart development / presynapse / cellular response to heat / actin cytoskeleton organization / fibroblast proliferation / regulation of gene expression
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsNaschberger A / Baradaran R
Funding support Austria, 3 items
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, 2021-
Header (metadata) releaseNov 17, 2021-
Map releaseNov 17, 2021-
UpdateJul 17, 2024-
Current statusJul 17, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 25
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 25
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7pgu
  • Surface level: 25
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13396.png

Downloads & links

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Map

FileDownload / File: emd_13396.map.gz / Format: CCP4 / Size: 396.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map generated from core-, GAP-SecPH- and tip-maps.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.46 Å/pix.
x 470 pix.
= 687.986 Å		1.46 Å/pix.
x 470 pix.
= 687.986 Å		1.46 Å/pix.
x 470 pix.
= 687.986 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.4638 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 30.0 / Movie #1: 25
Minimum - Maximum-86.088750000000005 - 163.131529999999998
Average (Standard dev.)0.012881287 (±1.4465549)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions470470470
Spacing470470470
CellA=B=C: 687.98596 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.46381.46381.4638
M x/y/z470470470
origin x/y/z0.0000.0000.000
length x/y/z687.986687.986687.986
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ470470470
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS470470470
D min/max/mean-86.089163.1320.013

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Supplemental data

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Mask #1

Fileemd_13396_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Consensus map sharpened with DeepEMhancer.

Fileemd_13396_additional_1.map
AnnotationConsensus map sharpened with DeepEMhancer.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_13396_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_13396_half_map_2.map
Projections & Slices
AxesZYX

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Sample components

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Entire : Homo-dimer of human Neurofibromin Isoform 2

EntireName: Homo-dimer of human Neurofibromin Isoform 2
Components
  • Complex: Homo-dimer of human Neurofibromin Isoform 2
    • Protein or peptide: Neurofibromin
  • Ligand: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
  • Ligand: ZINC ION
  • Ligand: water

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Supramolecule #1: Homo-dimer of human Neurofibromin Isoform 2

SupramoleculeName: Homo-dimer of human Neurofibromin Isoform 2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 640 KDa

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Macromolecule #1: Neurofibromin

MacromoleculeName: Neurofibromin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 319.757656 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAAHRPVEWV QAVVSRFDEQ LPIKTGQQNT HTKVSTEHNK ECLINISKYK FSLVISGLTT ILKNVNNMRI FGEAAEKNLY LSQLIILDT LEKCLAGQPK DTMRLDETML VKQLLPEICH FLHTCREGNQ HAAELRNSAS GVLFSLSCNN FNAVFSRIST R LQELTVCS ...String:
MAAHRPVEWV QAVVSRFDEQ LPIKTGQQNT HTKVSTEHNK ECLINISKYK FSLVISGLTT ILKNVNNMRI FGEAAEKNLY LSQLIILDT LEKCLAGQPK DTMRLDETML VKQLLPEICH FLHTCREGNQ HAAELRNSAS GVLFSLSCNN FNAVFSRIST R LQELTVCS EDNVDVHDIE LLQYINVDCA KLKRLLKETA FKFKALKKVA QLAVINSLEK AFWNWVENYP DEFTKLYQIP QT DMAECAE KLFDLVDGFA ESTKRKAAVW PLQIILLILC PEIIQDISKD VVDENNMNKK LFLDSLRKAL AGHGGSRQLT ESA AIACVK LCKASTYINW EDNSVIFLLV QSMVVDLKNL LFNPSKPFSR GSQPADVDLM IDCLVSCFRI SPHNNQHFKI CLAQ NSPST FHYVLVNSLH RIITNSALDW WPKIDAVYCH SVELRNMFGE TLHKAVQGCG AHPAIRMAPS LTFKEKVTSL KFKEK PTDL ETRSYKYLLL SMVKLIHADP KLLLCNPRKQ GPETQGSTAE LITGLVQLVP QSHMPEIAQE AMEALLVLHQ LDSIDL WNP DAPVETFWEI SSQMLFYICK KLTSHQMLSS TEILKWLREI LICRNKFLLK NKQADRSSCH FLLFYGVGCD IPSSGNT SQ MSMDHEELLR TPGASLRKGK GNSSMDSAAG CSGTPPICRQ AQTKLEVALY MFLWNPDTEA VLVAMSCFRH LCEEADIR C GVDEVSVHNL LPNYNTFMEF ASVSNMMSTG RAALQKRVMA LLRRIEHPTA GNTEAWEDTH AKWEQATKLI LNYPKAKME DGQAAESLHK TIVKRRMSHV SGGGSIDLSD TDSLQEWINM TGFLCALGGV CLQQRSNSGL ATYSPPMGPV SERKGSMISV MSSEGNADT PVSKFMDRLL SLMVCNHEKV GLQIRTNVKD LVGLELSPAL YPMLFNKLKN TISKFFDSQG QVLLTDTNTQ F VEQTIAIM KNLLDNHTEG SSEHLGQASI ETMMLNLVRY VRVLGNMVHA IQIKTKLCQL VEVMMARRDD LSFCQEMKFR NK MVEYLTD WVMGTSNQAA DDDVKCLTRD LDQASMEAVV SLLAGLPLQP EEGDGVELME AKSQLFLKYF TLFMNLLNDC SEV EDESAQ TGGRKRGMSR RLASLRHCTV LAMSNLLNAN VDSGLMHSIG LGYHKDLQTR ATFMEVLTKI LQQGTEFDTL AETV LADRF ERLVELVTMM GDQGELPIAM ALANVVPCSQ WDELARVLVT LFDSRHLLYQ LLWNMFSKEV ELADSMQTLF RGNSL ASKI MTFCFKVYGA TYLQKLLDPL LRIVITSSDW QHVSFEVDPT RLEPSESLEE NQRNLLQMTE KFFHAIISSS SEFPPQ LRS VCHCLYQATC HSLLNKATVK EKKENKKSVV SQRFPQNSIG AVGSAMFLRF INPAIVSPYE AGILDKKPPP RIERGLK LM SKILQSIANH VLFTKEEHMR PFNDFVKSNF DAARRFFLDI ASDCPTSDAV NHSLSFISDG NVLALHRLLW NNQEKIGQ Y LSSNRDHKAV GRRPFDKMAT LLAYLGPPEH KPVADTHWSS LNLTSSKFEE FMTRHQVHEK EEFKALKTLS IFYQAGTSK AGNPIFYYVA RRFKTGQING DLLIYHVLLT LKPYYAKPYE IVVDLTHTGP SNRFKTDFLS KWFVVFPGFA YDNVSAVYIY NCNSWVREY TKYHERLLTG LKGSKRLVFI DCPGKLAEHI EHEQQKLPAA TLALEEDLKV FHNALKLAHK DTKVSIKVGS T AVQVTSAE RTKVLGQSVF LNDIYYASEI EEICLVDENQ FTLTIANQGT PLTFMHQECE AIVQSIIHIR TRWELSQPDS IP QHTKIRP KDVPGTLLNI ALLNLGSSDP SLRSAAYNLL CALTCTFNLK IEGQLLETSG LCIPANNTLF IVSISKTLAA NEP HLTLEF LEECISGFSK SSIELKHLCL EYMTPWLSNL VRFCKHNDDA KRQRVTAILD KLITMTINEK QMYPSIQAKI WGSL GQITD LLDVVLDSFI KTSATGGLGS IKAEVMADTA VALASGNVKL VSSKVIGRMC KIIDKTCLSP TPTLEQHLMW DDIAI LARY MLMLSFNNSL DVAAHLPYLF HVVTFLVATG PLSLRASTHG LVINIIHSLC TCSQLHFSEE TKQVLRLSLT EFSLPK FYL LFGISKVKSA AVIAFRSSYR DRSFSPGSYE RETFALTSLE TVTEALLEIM EACMRDIPTC KWLDQWTELA QRFAFQY NP SLQPRALVVF GCISKRVSHG QIKQIIRILS KALESCLKGP DTYNSQVLIE ATVIALTKLQ PLLNKDSPLH KALFWVAV A VLQLDEVNLY SAGTALLEQN LHTLDSLRIF NDKSPEEVFM AIRNPLEWHC KQMDHFVGLN FNSNFNFALV GHLLKGYRH PSPAIVARTV RILHTLLTLV NKHRNCDKFE VNTQSVAYLA ALLTVSEEVR SRCSLKHRKS LLLTDISMEN VPMDTYPIHH GDPSYRTLK ETQPWSSPKG SEGYLAATYP TVGQTSPRAR KSMSLDMGQP SQANTKKLLG TRKSFDHLIS DTKAPKRQEM E SGITTPPK MRRVAETDYE METQRISSSQ QHPHLRKVSV SESNVLLDEE VLTDPKIQAL LLTVLATLVK YTTDEFDQRI LY EYLAEAS VVFPKVFPVV HNLLDSKINT LLSLCQDPNL LNPIHGIVQS VVYHEESPPQ YQTSYLQSFG FNGLWRFAGP FSK QTQIPD YAELIVKFLD ALIDTYLPGI DEETSEESLL TPTSPYPPAL QSQLSITANL NLSNSMTSLA TSQHSPGIDK ENVE LSPTT GHCNSGRTRH GSASQVQKQR SAGSFKRNSI KKIV

UniProtKB: Neurofibromin

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Macromolecule #2: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY...

MacromoleculeName: (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE
type: ligand / ID: 2 / Number of copies: 2 / Formula: PEV
Molecular weightTheoretical: 720.012 Da
Chemical component information

ChemComp-PEV:
(1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE / POPE, phospholipid*YM

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 300087
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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