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