title: Sites in the CH3 domain of human IgA1 that influence sensitivity to bacterial IgA1 proteases.
abstract: The influence of regions, other than the hinge, on the susceptibility of human IgA1 to cleavage by diverse bacterial IgA1 proteases, was examined using IgA1 mutants bearing amino acid deletions, substitutions, and domain swaps. IgA1 lacking the tailpiece retained its susceptibility to cleavage by all of the IgA1 proteases. The domain swap molecule alpha1alpha2gamma3, in which the CH3 domain of IgA1 was exchanged for that of human IgG1, was resistant to cleavage with the type 1 and 2 serine IgA1 proteases of Neisseria meningitidis, Neisseria gonorrhoeae, and Haemophilus influenzae, but remained sensitive to cleavage with the metallo-IgA1 proteases of Streptococcus pneumoniae, Streptococcus oralis, Streptococcus sanguis, and Streptococcus mitis. Substitution of the IgA1 Calpha3 domain motif Pro440 -Phe443 into the corresponding position in the Cgamma3 domain of alpha1alpha2gamma3 resulted now in sensitivity to the type 2 IgA1 protease of N. meningitidis, indicating the possible requirement of these amino acids for sensitivity to this protease. For the H. influenzae type 2 protease, resistance of an IgA1 mutant in which the CH3 domain residues 399-409 were exchanged with those from IgG1, but sensitivity of mutant HuBovalpha3 in which the Calpha3 domain of bovine IgA replaces that of human IgA1, suggests that CH3 domain residues Glu403, Gln406, and Thr409 influence sensitivity to this enzyme. Hence, unlike the situation with the metallo-IgA1 proteases of Streptococcus spp., the sensitivity of human IgA1 to cleavage with the serine IgA1 proteases of Neisseria and Haemophilus involves their binding to different sites specifically in the CH3 domain.
authors.affiliation: Division of Pathology and Neuroscience, University of Dundee Medical School, Ninewells Hospital, Dundee, United Kingdom.
authors.forename: Bernard W
authors.initials: BW
authors.lastname: Senior
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Woof
mesh_terms: D000595:Amino Acid Sequence; D001419:Bacteria / Q000201:enzymology*; D006193:Haemophilus influenzae / Q000201:enzymology; D006801:Humans; D006868:Hydrolysis; D007070:Immunoglobulin A / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009344:Neisseria gonorrhoeae / Q000201:enzymology; D009345:Neisseria meningitidis / Q000201:enzymology; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D034361:Streptococcus mitis / Q000201:enzymology; D019533:Streptococcus oralis / Q000201:enzymology; D013296:Streptococcus pneumoniae / Q000201:enzymology; D013298:Streptococcus sanguis / Q000201:enzymology; D013379:Substrate Specificity
chemical_list: D007070:Immunoglobulin A; D012697:Serine Endopeptidases; C021433:IgA-specific serine endopeptidase