9QDI

Crystal structure of BF3526 peptidase from Bacteroides fragilis in complex with a peptide

Summary for 9QDI

• Entry DOI: 10.2210/pdb9qdi/pdb
• Related: 9QDH
• Descriptor: Lipoprotein, Synthetic peptide SER-THR-PRO-PRO, POTASSIUM ION, ... (10 entities in total)
• Functional Keywords: iga protease, peptidase, protease, bf3526, m64, metallopeptidase, metalloprotease, antibody, ig, iga, bacteroides, metzincin, nephropathy, igan, hinge, complex, substrate, product, hydrolase
• Biological source: Bacteroides fragilis NCTC 9343; More
• Total number of polymer chains: 12
• Total formula weight: 373697.53

Authors

Martinez Gascuena, A.,Marquez-Monino, M.A.,Manzanares-Gomez, A.,Aguillo-Urarte, M.,Trastoy, B. (deposition date: 2025-03-06, release date: 2025-07-16, Last modification date: 2025-09-10)

Primary citation

Marquez-Monino, M.A.,Martinez Gascuena, A.,Azzam, T.,Persson, A.,Manzanares-Gomez, A.,Aguillo-Urarte, M.,Brown, T.T.,Montero-Sagarminaga, A.,Lood, R.,Naegeli, A.,Connell, S.R.,Sastre, D.E.,Sundberg, E.J.,Trastoy, B.
Molecular basis of Fab-dependent IgA antibody recognition by gut-bacterial metallopeptidases.
Embo J., 44:4867-4898, 2025

PubMed Abstract: 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 Bacteroides fragilis. Our structural, biochemical, and mutagenesis analyses demonstrate that ThomasA cleaves IgA through exclusive recognition of the Fab region. This mechanism is distinct from that of 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, combined with enzymology assays, show that this enzyme targets the N-terminus of pre-digested proteins, but does not act on intact IgA. These findings reveal divergent substrate recognition strategies between M64 family members, while providing new structural insights into their conserved catalytic mechanism.

PubMed: 40745064
DOI: 10.1038/s44318-025-00518-w

Experimental method

X-RAY DIFFRACTION (1.94 Å)