IgA1 protease cleaves heavy chains independently in dimeric human IgA1.

Bacterial IgA1 proteases have substrate specificity for human IgA1 immunoglobulin, and cleave both the heavy (alpha) chains where they are paired by disulfide bonds in the hinge region. To determine if the close apposition of the alpha chains allows a single enzyme-substrate-binding event to cleave both hinge region peptides we quantitated the relative levels of intermediate products during the course of complete hydrolysis of an IgA1 paraprotein. The substrate had four Fab regions, analogous to a secretory IgA dimer. The experimental data were then compared to computer-generated models in which various levels of cooperativity among Fab regions were tested. The results most closely conformed to a model in which each individual alpha chain is proteolyzed independently, without regard to the total number of hinge region peptides available in the substrate IgA1. These results will be used to guide the design of IgA1 hinge region peptide analogues as IgA1 protease inhibitors.