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- EMDB-27826: Cryo-EM structure of the full-length human NF1 dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-27826
TitleCryo-EM structure of the full-length human NF1 dimer
Map dataCryo-EM structure of the full-length human NF1 dimer
Sample
  • Complex: Full-length human NF1
    • Protein or peptide: Isoform I of Neurofibromin
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsDarling JE / Merk A / Grisshammer R / Ognjenovic J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.
Authors: Lucy C Young / Ruby Goldstein de Salazar / Sae-Won Han / Zi Yi Stephanie Huang / Alan Merk / Matthew Drew / Joseph Darling / Vanessa Wall / Reinhard Grisshammer / Alice Cheng / Madeline R ...Authors: Lucy C Young / Ruby Goldstein de Salazar / Sae-Won Han / Zi Yi Stephanie Huang / Alan Merk / Matthew Drew / Joseph Darling / Vanessa Wall / Reinhard Grisshammer / Alice Cheng / Madeline R Allison / Matthew J Sale / Dwight V Nissley / Dominic Esposito / Jana Ognjenovic / Frank McCormick /
Abstract: The majority of pathogenic mutations in the neurofibromatosis type I () gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well ...The majority of pathogenic mutations in the neurofibromatosis type I () gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.
History
DepositionAug 12, 2022-
Header (metadata) releaseApr 26, 2023-
Map releaseApr 26, 2023-
UpdateApr 26, 2023-
Current statusApr 26, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27826.png

Downloads & links

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Map

FileDownload / File: emd_27826.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of the full-length human NF1 dimer
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.0133
Minimum - Maximum-0.028608907 - 0.08274811
Average (Standard dev.)1.4790469e-07 (±0.0016794077)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 532.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of the full-length human NF1 dimer

Fileemd_27826_half_map_1.map
AnnotationCryo-EM structure of the full-length human NF1 dimer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of the full-length human NF1 dimer

Fileemd_27826_half_map_2.map
AnnotationCryo-EM structure of the full-length human NF1 dimer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Full-length human NF1

EntireName: Full-length human NF1
Components
  • Complex: Full-length human NF1
    • Protein or peptide: Isoform I of Neurofibromin

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Supramolecule #1: Full-length human NF1

SupramoleculeName: Full-length human NF1 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 320 kDa/nm

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Macromolecule #1: Isoform I of Neurofibromin

MacromoleculeName: Isoform I of Neurofibromin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 317.410812 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 VCHCLYQVVS QRFPQNSIGA VGSAMFLRFI NPAIVSPYEA GILDKKPPPR IERGLKLMSK ILQSIANHVL FTKEEHM RP FNDFVKSNFD AARRFFLDIA SDCPTSDAVN HSLSFISDGN VLALHRLLWN NQEKIGQYLS SNRDHKAVGR RPFDKMAT L LAYLGPPEHK PVADTHWSSL NLTSSKFEEF MTRHQVHEKE EFKALKTLSI FYQAGTSKAG NPIFYYVARR FKTGQINGD LLIYHVLLTL KPYYAKPYEI VVDLTHTGPS NRFKTDFLSK WFVVFPGFAY DNVSAVYIYN CNSWVREYTK YHERLLTGLK GSKRLVFID CPGKLAEHIE HEQQKLPAAT LALEEDLKVF HNALKLAHKD TKVSIKVGST AVQVTSAERT KVLGQSVFLN D IYYASEIE EICLVDENQF TLTIANQGTP LTFMHQECEA IVQSIIHIRT RWELSQPDSI PQHTKIRPKD VPGTLLNIAL LN LGSSDPS LRSAAYNLLC ALTCTFNLKI EGQLLETSGL CIPANNTLFI VSISKTLAAN EPHLTLEFLE ECISGFSKSS IEL KHLCLE YMTPWLSNLV RFCKHNDDAK RQRVTAILDK LITMTINEKQ MYPSIQAKIW GSLGQITDLL DVVLDSFIKT SATG GLGSI KAEVMADTAV ALASGNVKLV SSKVIGRMCK IIDKTCLSPT PTLEQHLMWD DIAILARYML MLSFNNSLDV AAHLP YLFH VVTFLVATGP LSLRASTHGL VINIIHSLCT CSQLHFSEET KQVLRLSLTE FSLPKFYLLF GISKVKSAAV IAFRSS YRD RSFSPGSYER ETFALTSLET VTEALLEIME ACMRDIPTCK WLDQWTELAQ RFAFQYNPSL QPRALVVFGC ISKRVSH GQ IKQIIRILSK ALESCLKGPD TYNSQVLIEA TVIALTKLQP LLNKDSPLHK ALFWVAVAVL QLDEVNLYSA GTALLEQN L HTLDSLRIFN DKSPEEVFMA IRNPLEWHCK QMDHFVGLNF NSNFNFALVG HLLKGYRHPS PAIVARTVRI LHTLLTLVN KHRNCDKFEV NTQSVAYLAA LLTVSEEVRS RCSLKHRKSL LLTDISMENV PMDTYPIHHG DPSYRTLKET QPWSSPKGSE GYLAATYPT VGQTSPRARK SMSLDMGQPS QANTKKLLGT RKSFDHLISD TKAPKRQEME SGITTPPKMR RVAETDYEME T QRISSSQQ HPHLRKVSVS ESNVLLDEEV LTDPKIQALL LTVLATLVKY TTDEFDQRIL YEYLAEASVV FPKVFPVVHN LL DSKINTL LSLCQDPNLL NPIHGIVQSV VYHEESPPQY QTSYLQSFGF NGLWRFAGPF SKQTQIPDYA ELIVKFLDAL IDT YLPGID EETSEESLLT PTSPYPPALQ SQLSITANLN LSNSMTSLAT SQHSPGIDKE NVELSPTTGH CNSGRTRHGS ASQV QKQRS AGSFKRNSIK KIV

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeJEOL CRYO ARM 200
Electron beamAcceleration voltage: 200 kV / Electron source: OTHER
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 9.6 e/Å2

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 692875

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