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- EMDB-21899: CryoEM structure of human SEMA6A dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-21899
TitleCryoEM structure of human SEMA6A dimer
Map data
Sample
  • Cell: SEMA6A dimer
    • Protein or peptide: SEMA6A
Function / homology
Function and homology information


negative regulation of cell adhesion involved in sprouting angiogenesis / semaphorin receptor binding / negative regulation of sprouting angiogenesis / Other semaphorin interactions / negative regulation of vascular endothelial growth factor signaling pathway / negative regulation of axon extension involved in axon guidance / positive regulation of neuron migration / chemorepellent activity / neural crest cell migration / negative chemotaxis ...negative regulation of cell adhesion involved in sprouting angiogenesis / semaphorin receptor binding / negative regulation of sprouting angiogenesis / Other semaphorin interactions / negative regulation of vascular endothelial growth factor signaling pathway / negative regulation of axon extension involved in axon guidance / positive regulation of neuron migration / chemorepellent activity / neural crest cell migration / negative chemotaxis / semaphorin-plexin signaling pathway / cellular response to vascular endothelial growth factor stimulus / cytoskeleton organization / negative regulation of angiogenesis / axon guidance / animal organ morphogenesis / negative regulation of ERK1 and ERK2 cascade / nervous system development / cell surface receptor signaling pathway / positive regulation of cell migration / axon / apoptotic process / extracellular space / membrane / plasma membrane
Similarity search - Function
Semaphorin / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / PSI domain / domain found in Plexins, Semaphorins and Integrins / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsKucharska I / Rubinstein JL / Julien JP
Funding support Canada, 3 items
OrganizationGrant numberCountry
Other governmentOntario Early Researcher Awards program Canada
Other governmentOntario Research Fund Canada
Other governmentCanada Foundation for Innovation Canada
CitationJournal: Cell / Year: 2020
Title: Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins.
Authors: Hunsang Lee / Greg L Beilhartz / Iga Kucharska / Swetha Raman / Hong Cui / Mandy Hiu Yi Lam / Huazhu Liang / John L Rubinstein / Daniel Schramek / Jean-Philippe Julien / Roman A Melnyk / Mikko Taipale /
Abstract: Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome ...Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% similar to C. difficile TcdB, which enters host cells via Frizzled receptors in colon epithelium. However, P. sordellii infections target vascular endothelium, suggesting that TcsL exploits another receptor. Here, using CRISPR/Cas9 screening, we establish semaphorins SEMA6A and SEMA6B as TcsL receptors. We demonstrate that recombinant SEMA6A can protect mice from TcsL-induced edema. A 3.3 Å cryo-EM structure shows that TcsL binds SEMA6A with the same region that in TcdB binds structurally unrelated Frizzled. Remarkably, 15 mutations in this evolutionarily divergent surface are sufficient to switch binding specificity of TcsL to that of TcdB. Our findings establish semaphorins as physiologically relevant receptors for TcsL and reveal the molecular basis for the difference in tissue targeting and disease pathogenesis between highly related toxins.
History
DepositionMay 3, 2020-
Header (metadata) releaseJul 8, 2020-
Map releaseJul 8, 2020-
UpdateJul 8, 2020-
Current statusJul 8, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 8.66
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 8.66
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_21899.map.gz / Format: CCP4 / Size: 4.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 8.66 / Movie #1: 8.66
Minimum - Maximum-23.617193 - 43.55709
Average (Standard dev.)0.74889517 (±3.949764)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin768677
Dimensions10993107
Spacing10710993
CellA: 110.21 Å / B: 112.27 Å / C: 95.79 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.031.031.03
M x/y/z10710993
origin x/y/z0.0000.0000.000
length x/y/z110.210112.27095.790
α/β/γ90.00090.00090.000
start NX/NY/NZ777686
NX/NY/NZ10710993
MAP C/R/S321
start NC/NR/NS867677
NC/NR/NS93109107
D min/max/mean-23.61743.5570.749

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Supplemental data

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Sample components

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Entire : SEMA6A dimer

EntireName: SEMA6A dimer
Components
  • Cell: SEMA6A dimer
    • Protein or peptide: SEMA6A

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Supramolecule #1: SEMA6A dimer

SupramoleculeName: SEMA6A dimer / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: SEMA6A

MacromoleculeName: SEMA6A / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ET GFPEDSE PISISHGNYT KQYPVFVGHK PGRNTTQRHR LDIQM IMIM NGTLYIAARD HIYTVDIDTS HTEEIYCSKK LTWKSRQADV DTCRMKGKHK DECHNF IKV LLKKNDDALF VCGTNAFNPS CRNYKMDTLE PFGDEFSGMA RCPYDAKHAN VALFADG KL ...String:
ET GFPEDSE PISISHGNYT KQYPVFVGHK PGRNTTQRHR LDIQM IMIM NGTLYIAARD HIYTVDIDTS HTEEIYCSKK LTWKSRQADV DTCRMKGKHK DECHNF IKV LLKKNDDALF VCGTNAFNPS CRNYKMDTLE PFGDEFSGMA RCPYDAKHAN VALFADG KL YSATVTDFLA IDAVIYRSLG ESPTLRTVKH DSKWLKEPYF VQAVDYGDYI YFFFREIA V EYNTMGKVVF PRVAQVCKND MGGSQRVLEK QWTSFLKARL NCSVPGDSHF YFNILQAVT DVIRINGRDV VLATFSTPYN SIPGSAVCAY DMLDIASVFT GRFKEQKSPD STWTPVPDER VPKPRPGCC AGSSSLERYA TSNEFPDDTL NFIKTHPLMD EAVPSIFNRP WFLRTMVRYR L TKIAVDTA AGPYQNHTVV FLGSEKGIIL KFLARIGNSG FLNDSLFLEE MSVYNSEKCS YD GVEDKRI MGMQLDRASS SLYVAFSTCV IKVPLGRCER YGKCKKTCIA SRDPYCGWIK EGG ACSHLS PNSRLTFEQD IERGNTDGLG DCHN GSWSH PQFEK

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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
GridDetails: unspecified
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: OTHER / Average electron dose: 45.24 e/Å2 / Details: Images were collected with FEI Falcon IV.
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 2)
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2) / Number images used: 281207
DetailsFEI Falcon IV

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Atomic model buiding 1

Initial modelPDB ID:

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