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- EMDB-11814: The cryo-EM structure of the Vag8-C1 inhibitor complex -

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Basic information

Entry
Database: EMDB / ID: EMD-11814
TitleThe cryo-EM structure of the Vag8-C1 inhibitor complex
Map datapost-processed final volume
Sample
  • Complex: Vag8:C1 inhibitor complex
    • Protein or peptide: Plasma protease C1 inhibitor
    • Protein or peptide: Vag8
Function / homology
Function and homology information


negative regulation of complement activation, lectin pathway / Defective SERPING1 causes hereditary angioedema / outer membrane / blood circulation / complement activation, classical pathway / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / platelet alpha granule lumen / Regulation of Complement cascade / serine-type endopeptidase inhibitor activity ...negative regulation of complement activation, lectin pathway / Defective SERPING1 causes hereditary angioedema / outer membrane / blood circulation / complement activation, classical pathway / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / platelet alpha granule lumen / Regulation of Complement cascade / serine-type endopeptidase inhibitor activity / blood coagulation / Platelet degranulation / collagen-containing extracellular matrix / blood microparticle / endoplasmic reticulum lumen / innate immune response / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
Pertactin virulence factor family / Pertactin, central region / Pertactin / Autotransporter beta-domain / Outer membrane autotransporter barrel / Autotransporter beta-domain / Autotransporter beta-domain profile. / Autotransporter beta-domain / Autotransporter beta-domain superfamily / Autotransporter, pectate lyase C-like domain superfamily ...Pertactin virulence factor family / Pertactin, central region / Pertactin / Autotransporter beta-domain / Outer membrane autotransporter barrel / Autotransporter beta-domain / Autotransporter beta-domain profile. / Autotransporter beta-domain / Autotransporter beta-domain superfamily / Autotransporter, pectate lyase C-like domain superfamily / Serpin, conserved site / Serpins signature. / Serpin superfamily, domain 2 / Serpin family / Serpin domain / Serpin superfamily / Serpin superfamily, domain 1 / Serpin (serine protease inhibitor) / SERine Proteinase INhibitors / Pectin lyase fold/virulence factor
Similarity search - Domain/homology
Vag8 / Plasma protease C1 inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human) / Bordetella pertussis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsJohnson S / Lea SM / Deme JC / Furlong E / Dhillon A
Funding support United Kingdom, 4 items
OrganizationGrant numberCountry
Wellcome Trust100298 United Kingdom
Wellcome Trust209194 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/M011984/1 United Kingdom
Wellcome Trust219477 United Kingdom
CitationJournal: mBio / Year: 2021
Title: Molecular Basis for Bordetella pertussis Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex.
Authors: Arun Dhillon / Justin C Deme / Emily Furlong / Dorina Roem / Ilse Jongerius / Steven Johnson / Susan M Lea /
Abstract: Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key ...Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, , was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8-C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases. The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.
History
DepositionOct 2, 2020-
Header (metadata) releaseJun 16, 2021-
Map releaseJun 16, 2021-
UpdateJun 16, 2021-
Current statusJun 16, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0122
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.0122
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7akv
  • Surface level: 0.0122
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11814.png

Downloads & links

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Map

FileDownload / File: emd_11814.map.gz / Format: CCP4 / Size: 134.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpost-processed final volume
Voxel sizeX=Y=Z: 0.828 Å
Density
Contour LevelBy AUTHOR: 0.0122 / Movie #1: 0.0122
Minimum - Maximum-0.038749307 - 0.055746492
Average (Standard dev.)7.2586925e-05 (±0.0011971341)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions328328328
Spacing328328328
CellA=B=C: 271.584 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8280.8280.828
M x/y/z328328328
origin x/y/z0.0000.0000.000
length x/y/z271.584271.584271.584
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS328328328
D min/max/mean-0.0390.0560.000

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Supplemental data

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Mask #1

Fileemd_11814_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: refinement volume

Fileemd_11814_additional_1.map
Annotationrefinement volume
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Additional map: relion local resolution filtered volume

Fileemd_11814_additional_2.map
Annotationrelion local resolution filtered volume
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: second half map

Fileemd_11814_half_map_1.map
Annotationsecond half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: first half map

Fileemd_11814_half_map_2.map
Annotationfirst half map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Vag8:C1 inhibitor complex

EntireName: Vag8:C1 inhibitor complex
Components
  • Complex: Vag8:C1 inhibitor complex
    • Protein or peptide: Plasma protease C1 inhibitor
    • Protein or peptide: Vag8

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Supramolecule #1: Vag8:C1 inhibitor complex

SupramoleculeName: Vag8:C1 inhibitor complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 100 KDa

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Macromolecule #1: Plasma protease C1 inhibitor

MacromoleculeName: Plasma protease C1 inhibitor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.011637 KDa
Recombinant expressionOrganism: Drosophila albipalpis (fry)
SequenceString: PTIQPTQPTT QLPTDSPTQP TTGSFCPGPV TLCSDLESHS TEAVLGDALV DFSLKLYHAF SAMKKVETNM AFSPFSIASL LTQVLLGAG ENTKTNLESI LSYPKDFTCV HQALKGFTTK GVTSVSQIFH SPDLAIRDTF VNASRTLYSS SPRVLSNNSD A NLELINTW ...String:
PTIQPTQPTT QLPTDSPTQP TTGSFCPGPV TLCSDLESHS TEAVLGDALV DFSLKLYHAF SAMKKVETNM AFSPFSIASL LTQVLLGAG ENTKTNLESI LSYPKDFTCV HQALKGFTTK GVTSVSQIFH SPDLAIRDTF VNASRTLYSS SPRVLSNNSD A NLELINTW VAKNTNNKIS RLLDSLPSDT RLVLLNAIYL SAKWKTTFDP KKTRMEPFHF KNSVIKVPMM NSKKYPVAHF ID QTLKAKV GQLQLSHNLS LVILVPQNLK HRLEDMEQAL SPSVFKAIME KLEMSKFQPT LLTLPRIKVT TSQDMLSIME KLE FFDFSY DLNLCGLTED PDLQVSAMQH QTVLELTETG VEAAAASAIS VARTLLVFEV QQPFLFVLWD QQHKFPVFMG RVYD PRA

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Macromolecule #2: Vag8

MacromoleculeName: Vag8 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bordetella pertussis (bacteria)
Molecular weightTheoretical: 91.262172 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: AVTAAQRIDG GAAFLGDVAI ATTKASEHGI NVTGRTAEVR VTGGTIRTSG NQAQGLRVGT ENAPDNTAVV ASVFLQNLII ETSGTGALG VSVHEPQGGG GTRLSMSGTT VRTRGDDSFA LQLSGPASAT LNDVALETAG QQAPAVVLWQ GAQLNAQGLV V QVNGAGVS ...String:
AVTAAQRIDG GAAFLGDVAI ATTKASEHGI NVTGRTAEVR VTGGTIRTSG NQAQGLRVGT ENAPDNTAVV ASVFLQNLII ETSGTGALG VSVHEPQGGG GTRLSMSGTT VRTRGDDSFA LQLSGPASAT LNDVALETAG QQAPAVVLWQ GAQLNAQGLV V QVNGAGVS AIHAQDAGSF TLSGSDITAR GLEVVGIYVQ EGMQGTLTGT RVTTQGDTAP ALQVEDAGTH VSMNGGALST SG ANSPAAW LLAGGSAQFR DTVLRTVGEA SHGVDVAAHS EVELAHAQVR ADGQGAHGLV VTRSSAMVRA GSLVESTGDG AAA LLESGH LTVDGSVVHG HGAAGLEVDG ESNVSLLNGA RLSSDQPTAI RLIDPRSVLN LDIKDRAQLL GDIAPEAQQP DGSP EQARV RVALADGGTW AGRTDGAVHT VRLLDRGVWT VTGDSRVAEV KLEGGTLAFA PPAQPKGAFK TLVATQGISG TGTIV MNAH LPSGTADVLV APQGFGDRQV LVVNNTDDGT ESGATKVPLI EDEQGHTAFT LGNMGGRVDA GARQYELTAS EAQADK ART WQLTPTNELS TTATAAVNAM AIAASQRIWQ AEMDVLLRHM SGLHSIGSPG GFWARGLSQR QRLDTGYGPW QKQTVSG IE LGLDRRVAGG ATTAWSVGML AGYSETRRDG GAYRAGHVHS AHVGAYVSYL NDSGSYVDGV VKYNRFRHGF DIRTTDLK R VDAKHRSHGL GALLRGGRRI DIDGGWYVEP QASVAWFHAG GSRYEASNGL RVRADGAHSW VLRAGAEAGR QMRLANGNI VEPYARLGWA QELGADNAVY TNGIRHVTRS RGGFAEARVG VGALLGKRHA LYADYEYAKG ARFEAPWTLQ LGYRYSW

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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

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: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 17261358
CTF correctionSoftware - Name: SIMPLE (ver. 3.0)
Initial angle assignmentType: COMMON LINE / Software - Name: SIMPLE (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 687883
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-7akv:
The cryo-EM structure of the Vag8-C1 inhibitor complex

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