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Structure of the Thomasclavelia ramosa immunoglobulin A protease reveals a modular and minimizable architecture distinct from other immunoglobulin A proteases

Tran, N.; Frenette, A.; Holyoak, T.

2025-01-02 biochemistry
10.1101/2024.12.31.630911 bioRxiv
Show abstract

Immunoglobulin A proteases (IgAPs) are a diverse group of enzymes secreted from bacteria that inhabit human mucosal tissues. These enzymes have convergently evolved to cleave human immunoglobulin A as a means of modulating and evading host immunity. Only two of three known IgAP families have been biochemically characterized beyond their initial discovery. Here, we show using solution-scattering, steady-state kinetic, and crystallographic approaches that the protease from Thomasclavelia ramosa, representing the uncharacterized third family, has a truly modular and minimizable protein architecture. This analysis also revealed a unique metal-associated domain that likely functions as a molecular spacer and generated a working hypothesis detailing the structural mechanism behind the enzymes high substrate specificity. Our work provides the first in-depth biochemical account of this IgAP family, paving the way for advancing clinically relevant IgAP-related research and our understanding of IgAPs as a whole.

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