Dataset Information

Molecular basis of Fab-dependent IgA antibody recognition by gut-associated metallopeptidases

ABSTRACT: Immunoglobulin A (IgA) is essential for mucosal immunity and is implicated in autoimmune diseases like IgA nephropathy (IgAN). Certain pathogenic and commensal bacteria produce IgA proteases (IgAPs) that selectively cleave IgA, potentially aiding bacterial colonization and offering therapeutic avenues for IgAN. Here, we investigate the substrate specificity of M64 family peptidases, focusing on the IgAP ThomasA from Thomasclavelia ramosa and BF3526 from Bacteroides fragilis. Structural, biochemical, and mutagenesis data demonstrate that ThomasA cleaves IgA through exclusive recognition of the Fab region—a mechanism distinct from other antibody-specific peptidases, which typically require engagement of the Fc region. In contrast, X-ray crystal structures of BF3526 in complex with substrate and product peptides, together with enzymology assays, show that this enzyme targets the N-terminus of predigested proteins. These findings reveal divergent substrate recognition strategies within the M64 family and provide structural insight into their conserved catalytic mechanism. Together, they enhance our understanding of bacterial adaptation and support the rational design of enzymes for IgA-mediated autoimmune diseases. The LC-MS data associated with the project is included in the current dataset.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Andrea Persson

LAB HEAD: Beatrice Trastoy

PROVIDER: PXD065112 | Pride | 2025-08-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	EV1_LC-MS_BF3526_0min_1to100.mzML	Mzml
	EV1_LC-MS_BF3526_1h_1to1000.mzML	Mzml
	EV1_LC-MS_BF3526_1h_1to10000.mzML	Mzml
	EV1_LC-MS_BF3526_2h_1to1000.mzML	Mzml
	EV1_LC-MS_BF3526_30min_1to100.mzML	Mzml

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Publications

Molecular basis of Fab-dependent IgA antibody recognition by gut-bacterial metallopeptidases.

Márquez-Moñino María Ángeles MÁ Martínez Gascueña Ana A Azzam Tala T Persson Andrea A Manzanares-Gomez Aitor A Aguillo-Urarte Marina M Brown Trenton T TT Montero-Sagarminaga Ainhoa A Lood Rolf R Naegeli Andreas A Connell Sean R SR Sastre Diego E DE Sundberg Eric J EJ Trastoy Beatriz B

The EMBO journal 20250731

Immunoglobulin A (IgA) is essential for mucosal immunity and has been implicated in autoimmune diseases, such as IgA nephropathy. Certain pathogenic and commensal bacteria produce IgA proteases that selectively cleave IgA, potentially aiding bacterial colonization as well as suggesting therapeutic avenues for IgA nephropathy. Here, we investigate the substrate specificities of two enzymes of the M64 metallopeptidase family, the IgA protease ThomasA from Thomasclavelia ramosa and BF3526 from Bact ...[more]

PMID: 40745064

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Project description:Oral biofilms, comprising hundreds of bacteria and other microorganisms on oral mucosal and dental surfaces, play a central role in oral health and disease dynamics. Streptococcus oralis, a key constituent of these biofilms, contribute significantly to their formation, serving as an early colonizer and microcolony scaffold. The interaction between S. oralis and the orally predominant mucin, MUC5B, is pivotal in biofilm development, yet the mechanism underlying MUC5B degradation remains poorly understood. This study introduces MdpS (Mucin Degrading Protease from Streptococcus oralis), a protease that extensively hydrolyses MUC5B and offers an insight into its sequence homology, physicochemical properties, and substrate- and amino acid specificity. MdpS exhibits high sequence conservation within the species and also explicitly among early biofilm colonizing streptococci. It is characterized as a calcium or magnesium dependent serine protease with strict physicochemical preferences, including narrow pH and temperature tolerance, and high sensitivity to increased sodium chloride and reducing agent concentrations. Furthermore, MdpS primarily hydrolyze proteins with O-glycans, but also show activity towards immunoglobulins IgA1/2 and IgM, suggesting potential immunomodulatory effects. Significantly, MdpS extensively degrades MUC5B in the N- and C-terminal domains, emphasizing its role in mucin degradation with implications in carbon and nitrogen sequestration for S. oralis with a potential function by cross-feeding the oral biofilm. Moreover, the enzyme displays amino acid preferences of serine, threonine or cysteine depending on substrate glycosylation. Understanding the interplay between S. oralis and MUC5B, facilitated by MdpS, has significant implications for the management of a healthy eubiotic oral microenvironment, offering potential targets for interventions aimed at modulating oral biofilm composition and succession. Additionally, the MdpS data challenges the presently acknowledged model of MUC5B degradation, because contrarily MdpS does not necessitate O-glycan removal prior to extensive peptide backbone hydrolysis. These findings emphasize the necessity for further research in this field.