A "knob-in-hole" gate in the antibody C(H)1 domain underlies subclass-independent IgA hinge cleavage by the commensal metallopeptidase IgAse.

A "knob-in-hole" gate mechanism in the CH1 domain underpins subclass-independent IgA hinge cleavage by IgAse.

• Why it matters: Understanding how bacterial IgA-peptidases subvert mucosal immunity is crucial, especially since IgAse can target both IgA1 and IgA2 subclasses, unlike other peptidases that only cleave IgA1. This knowledge could inform strategies to protect mucosal surfaces from bacterial invasion.
• What they did: The study used single-particle cryoelectron microscopy to analyze the IgAse:IgA2 F ab ' complex, revealing two states along the cleavage pathway, and identified a CH1-mediated "gate" involving a knob-in-hole interaction that facilitates hinge access.
• The result: The findings define a structural "gate" mechanism validated by crystal structures, mutations, and molecular dynamics, providing a framework for subclass-independent IgA cleavage and advancing understanding of bacterial immune evasion.