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

• 成果类型: Article
• 署名作者: Tran, Norman; Frenette, Aaron; Holyoak, Todd
• 署名单位: University of Waterloo
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10759
• DOI: 10.1073/pnas.2503549122
• 发表日期: 2025-09-02
• 关键词: x-ray-scattering; iga protease; haemophilus-influenzae; neisseria-gonorrhoeae; clostridium-ramosum; enzyme; proteins; specificity; complexes; allotype

摘要

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 enzyme's high substrate specificity. Our work provides an 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.