Structural motifs suggestive of hydrolytic activity are common among three-dimensional antibody structures (IRM9P.722)

Abstract

Abstract Naturally occurring catalytic antibodies are associated with both positive and negative outcomes in autoimmune disease and infection, but their function and prevalence remain unclear. Two monoclonal antibodies to Cryptococcus neoformans were shown to hydrolyze several peptide antigen mimetics. These two antibodies had distinct peptide hydrolysis patterns, which were altered, but not blocked, by alanine substitution of peptide residues, indicating a non-sequence-specific mechanism. A putative serine-protease-like active site was identified in the light chain variable region of both molecules. A computational algorithm was developed to detect similar sites present in other antibody structures. A three-dimensional reference template corresponding to the putative active site was optimally superposed with all possible templates in the other antibody structures. Hits were defined as those superpositions with an RMSD ≤ 1Å. The putative site was found in 24 of 80 known catalytic antibody structures and was found in 126 of 1367 studied antibodies with no annotation of catalytic activity. The ability of many antibodies to cleave antigen, albeit slowly, would provide a new function to immunoglobulin molecules in host defense. Confirmation of this active site is being pursued through site-directed mutagenesis. We anticipate that these studies will provide insights into the design of anti-cryptococcal therapies and the role of catalysis as a function of humoral immunity.