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- EMDB-52972: Cryo-EM structure of Thomasclavelia ramosa IgA peptidase (IgAse) ... -

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Basic information

Entry
Database: EMDB / ID: EMD-52972
TitleCryo-EM structure of Thomasclavelia ramosa IgA peptidase (IgAse) active site mutant (S32-N876)
Map data
Sample
  • Organelle or cellular component: Monomeric IgA peptidase active site mutant - E540A including the N-terminal domain
    • Protein or peptide: IgA protease
  • Ligand: ZINC ION
  • Ligand: GLYCEROL
  • Ligand: AZIDE ION
  • Ligand: water
KeywordsProtease / Metallopeptidase / Metzincin / HYDROLASE
Function / homology
Function and homology information


cellulose catabolic process / metallopeptidase activity / proteolysis / extracellular region / membrane
Similarity search - Function
Domain of unknown function DUF6273 / Domain of unknown function (DUF6273) / Peptidase M64, IgA / IgA Peptidase M64 / Carbohydrate binding X2 domain / Carbohydrate binding domain X2 / LPXTG cell wall anchor motif / LPXTG cell wall anchor domain / Metallopeptidase, catalytic domain superfamily / Immunoglobulin E-set / Immunoglobulin-like fold
Similarity search - Domain/homology
Biological speciesThomasclavelia ramosa (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsRamirez-Larrota JS / Eckhard U / Guerra P / Juyoux P / Gomis-Ruth FX
Funding support Spain, 3 items
OrganizationGrant numberCountry
Agencia Estatal de Investigacion (AEI)PRE2020-096731 Spain
Agencia Estatal de Investigacion (AEI)PID2019-107725RB-I00 Spain
Agencia Estatal de Investigacion (AEI)RYC2020-029773-I Spain
CitationJournal: PLoS Pathog / Year: 2025
Title: Biochemical and structural characterization of the human gut microbiome metallopeptidase IgAse provides insight into its unique specificity for the Fab' region of IgA1 and IgA2.
Authors: Juan Sebastián Ramírez-Larrota / Pauline Juyoux / Pablo Guerra / Ulrich Eckhard / F Xavier Gomis-Rüth /
Abstract: Human immunoglobulin A (IgA), comprising the isotypes IgA1 and IgA2, protects ~400 m2 of mucosal surfaces against microbial infections but can also lead to aberrant IgA deposits that cause disease. ...Human immunoglobulin A (IgA), comprising the isotypes IgA1 and IgA2, protects ~400 m2 of mucosal surfaces against microbial infections but can also lead to aberrant IgA deposits that cause disease. Certain bacteria have evolved peptidases that cleave the hinge between the Fab and Fc fragments of IgA, undermining its immune function. These peptidases specifically target IgA1, but not IgA2, which predominates in the gut and possesses a structurally distinct hinge region. The only known IgA2-specific peptidase is IgAse from the gut microbiome member Thomasclavelia ramosa, which also targets IgA1 but no other proteins. IgAse is a ~ 140-kDa, seven-domain, membrane-bound metallopeptidase (MP). Differential scanning fluorimetry, small-angle X-ray scattering, AI-based structural predictions, mass spectrometry, and high-resolution crystallography and cryo-electron microscopy of multidomain fragments of IgAse revealed a novel 313-residue catalytic domain (CD) from the igalysin family within the metzincin MP clan. The CD is flanked by an N-terminal globular C-type lectin-like domain and a wrapping domain (WD), followed by four all-β domains. Functional studies involving a comprehensive set of constructs (wild-type and mutant), authentic and recombinant IgA fragments, and inhibitors demonstrated that the minimal functional assembly requires the CD and WD, along with the Fab and hinge region (Fab'). Modelling studies suggested that the Fab heavy-chain constant domain interacts with the N-terminal subdomain of the CD, positioning the hinge peptide for cleavage-a mechanism confirmed by mutational analysis. These findings open avenues for therapeutic strategies to inhibit the only known IgA1/IgA2 peptidase and to develop it for dissolving pathologic IgA deposits.
History
DepositionFeb 27, 2025-
Header (metadata) releaseJun 25, 2025-
Map releaseJun 25, 2025-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52972.png

Downloads & links

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Map

FileDownload / File: emd_52972.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 320 pix.
= 233.6 Å		0.73 Å/pix.
x 320 pix.
= 233.6 Å		0.73 Å/pix.
x 320 pix.
= 233.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.029
Minimum - Maximum-0.2222569 - 0.42293027
Average (Standard dev.)0.00019271745 (±0.010342039)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 233.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_52972_additional_1.map
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Half map: #2

Fileemd_52972_half_map_1.map
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Half map: #1

Fileemd_52972_half_map_2.map
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Sample components

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Entire : Monomeric IgA peptidase active site mutant - E540A including the ...

EntireName: Monomeric IgA peptidase active site mutant - E540A including the N-terminal domain
Components
  • Organelle or cellular component: Monomeric IgA peptidase active site mutant - E540A including the N-terminal domain
    • Protein or peptide: IgA protease
  • Ligand: ZINC ION
  • Ligand: GLYCEROL
  • Ligand: AZIDE ION
  • Ligand: water

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Supramolecule #1: Monomeric IgA peptidase active site mutant - E540A including the ...

SupramoleculeName: Monomeric IgA peptidase active site mutant - E540A including the N-terminal domain
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Thomasclavelia ramosa (bacteria)

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Macromolecule #1: IgA protease

MacromoleculeName: IgA protease / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Thomasclavelia ramosa (bacteria)
Molecular weightTheoretical: 128.08225 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MASKPDIKVG DYVKMGVYNN ASILWRCVSI DNNGPLMLAD KIVDTLAYDA KTNDNSNSKS HSRSYKRDDY GSNYWKDSNM RSWLNSTAA EGKVDWLCGN PPKDGYVSGV GAYNEKAGFL NAFSKSEIAA MKTVTQRSLV SHPEYNKGIV DGDANSDLLY Y TDISEAVA ...String:
MASKPDIKVG DYVKMGVYNN ASILWRCVSI DNNGPLMLAD KIVDTLAYDA KTNDNSNSKS HSRSYKRDDY GSNYWKDSNM RSWLNSTAA EGKVDWLCGN PPKDGYVSGV GAYNEKAGFL NAFSKSEIAA MKTVTQRSLV SHPEYNKGIV DGDANSDLLY Y TDISEAVA NYDSSYFETT TEKVFLLDVK QANAVWKNLK GYYVAYNNDG MAWPYWLRTP VTD(CME)NHDMRY ISSSGQVG R YAPWYSDLGV RPAFYLDSEY FVTTSGSGSQ SSPYIGSAPN KQEDDYTISE PAEDANPDWN VSTEQSIQLT LGPWYSNDG KYSNPTIPVY TIQKTRSDTE NMVVVVCGEG YTKSQQGKFI NDVKRLWQDA MKYEPYRSYA DRFNVYALCT ASESTFDNGG STFFDVIVD KYNSPVISNN LHGSQWKNHI FERCIGPEFI EKIHDAHIKK KCDPNTIPSG SEYEPYYYVH DYIAQFAMVV N TKSDFGGA YNNREYGFHY FISPSDSYRA SKTFAHAFGH GLLGLGDEYS NGYLLDDKEL KSLNLSSVED PEKIKWRQLL GF RNTYTCR NAYGSKMLVS SYECIMRDTN YQFCEVCRLQ GFKRMSQLVK DVDLYVATPE VKEYTGAYSK PSDFTDLETS SYY NYTYNR NDRLLSGNSK SRFNTNMNGK KIELRTVIQN ISDKNARQLK FKMWIKHSDG SVATDSSGNP LQTVQTFDIP VWND KANFW PLGALDHIKS DFNSGLKSCS LIYQIPSDAQ LKSGDTVAFQ VLDENGNVLA DDNTETQRYT TVSIQYKFED GSEIP NTAG GTFTVPYGTK LDLTPAKTLY DYEFIKVDGL NKPIVSDGTV VTYYYKNKNE EHTHNLTLVA AKAATCTTAG NSAYYT CDG CDKWFADATG SVEITDKTSV KIPAPGHTAG TEWKSDDTNH WHECTVAGCG VIIESTKSAH TAGEWIVDTP ATATTAG TK HKECTVCHRV LETQPIPSTG TELKIIAGDN QIYNKASGSD VTITCNGDFA KFTGIKVDGS VVDSSNYTAV SGSTVLTL K ASYLGTLTDG SHTITFVYTD GEANANLTVR TAGSGHIHDY GTEWKSNADN HWHECNCGDK KDEAAHSFKW VVDKEATAT KKGSKHEECK ICGYKRSAVE ILEHHHHHH

UniProtKB: IgA protease

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Macromolecule #2: ZINC ION

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

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Macromolecule #3: GLYCEROL

MacromoleculeName: GLYCEROL / type: ligand / ID: 3 / Number of copies: 1 / Formula: GOL
Molecular weightTheoretical: 92.094 Da
Chemical component information

ChemComp-GOL:
GLYCEROL

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Macromolecule #4: AZIDE ION

MacromoleculeName: AZIDE ION / type: ligand / ID: 4 / Number of copies: 7 / Formula: AZI
Molecular weightTheoretical: 42.02 Da
Chemical component information

ChemComp-AZI:
AZIDE ION

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 151 / 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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 312476
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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