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- PDB-9qa6: Cryo-EM structure of Thomasclavelia ramosa IgA peptidase (IgAse) ... -

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Basic information

Entry
Database: PDB / ID: 9qa6
TitleCryo-EM structure of Thomasclavelia ramosa IgA peptidase (IgAse) active site mutant (S32-N876)
ComponentsIgA protease
KeywordsHYDROLASE / Protease / Metallopeptidase / Metzincin
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
AZIDE ION / IgA protease
Similarity search - Component
Biological speciesThomasclavelia ramosa (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsRamirez-Larrota, J.S. / Eckhard, U. / Guerra, P. / Juyoux, P. / Gomis-Ruth, F.X.
Funding support Spain, 3items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: IgA protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,66512
Polymers128,0821
Non-polymers58211
Water2,720151
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein IgA protease


Mass: 128082.250 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Thomasclavelia ramosa (bacteria) / Gene: iga / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9AES2
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-AZI / AZIDE ION


Mass: 42.020 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: N3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 151 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Monomeric IgA peptidase active site mutant - E540A including the N-terminal domain
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Thomasclavelia ramosa (bacteria)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 312476 / Symmetry type: POINT

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