Cleavage of the Hormone Human Chorionic Gonadotropin, by the Type 1 IgA1 Protease of<i>Neisseria gonorrhoeae,</i>and Its Implications

Senior, B. W.; Stewart, Wilson W.; Galloway, Claire R.; Kerr, Michael A.

doi:10.1086/323397

Cited by 21 publications

(18 citation statements)

References 15 publications

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“…Evidence of in vivo production of IgA1 proteases in human infections (4 -6), the association of recovery from infection with the development of Abs to IgA1 proteases (7)(8)(9), and the failure of related but nonpathogenic species of bacteria to produce IgA1 proteases (10,11) all point to IgA1 proteases being important virulence factors of the pathogens that produce them. Despite these persuasive indirect observations, the in vivo roles of IgA1 proteases in virulence are difficult to determine, because the substrate is restricted almost exclusively (12)(13)(14)(15) to IgA1 of humans, gorillas, and chimpanzees, and IgA of orangutans (16), and therefore convenient animal models are not available. However, IgA1 protease has been shown to compromise IgA-mediated killing of S. pneumoniae both in vitro and in vivo (17).…”

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confidence: 99%

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Sites in the CH3 Domain of Human IgA1 That Influence Sensitivity to Bacterial IgA1 Proteases

Senior

Woof

2006

The Journal of Immunology

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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 α1α2γ3, 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 Cα3 domain motif Pro440-Phe443 into the corresponding position in the Cγ3 domain of α1α2γ3 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 HuBovα3 in which the Cα3 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.

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“…Moreover, the Fab formed may mask relevant epitopes from the immune system and thus prevent the binding of intact Abs of other isotypes (19,20), activation of complement, and complement-mediated lysis. Some IgA1 proteases may have a role in virulence by mechanisms additional to or distinct from those arising through IgA1 cleavage (13,15,21).…”

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Sites in the CH3 Domain of Human IgA1 That Influence Sensitivity to Bacterial IgA1 Proteases

Senior

Woof

2006

The Journal of Immunology

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“…However, because the substrate for IgA1 proteases is restricted almost exclusively (15)(16)(17) to IgA1 from human, gorilla, chimpanzee, and the IgA of the orangutan (18), it is difficult to prove that IgA1 proteases are virulence factors in vivo. However, IgA1 protease has recently been shown to give in vivo and in vitro protection against IgA-mediated killing of S. pneumoniae (19).…”

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The Influences of Hinge Length and Composition on the Susceptibility of Human IgA to Cleavage by Diverse Bacterial IgA1 Proteases

Senior

Woof

2005

The Journal of Immunology

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The influences of IgA hinge length and composition on its susceptibility to cleavage by bacterial IgA1 proteases were examined using a panel of IgA hinge mutants. The IgA1 proteases of Streptococcus pneumoniae, Streptococcus sanguis strains SK4 and SK49, Neisseria meningitidis, Neisseria gonorrhoeae, and Haemophilus influenzae cleaved IgA2-IgA1 half hinge, an Ab featuring half of the IgA1 hinge incorporated into the equivalent site in IgA1 protease-resistant IgA2, whereas those of Streptococcus mitis, Streptococcus oralis, and S. sanguis strain SK1 did not. Hinge length reduction by removal of two of the four C-terminal proline residues rendered IgA2-IgA1 half hinge resistant to all streptococcal IgA1 metalloproteinases but it remained sensitive to cleavage by the serine-type IgA1 proteases of Neisseria and Haemophilus spp. The four C-terminal proline residues could be substituted by alanine residues or transferred to the N-terminal extremity of the hinge without affect on the susceptibility of the Ab to cleavage by serine-type IgA1 proteases. However, their removal rendered the Ab resistant to cleavage by all the IgA1 proteases. We conclude that the serine-type IgA1 proteases of Neisseria and Haemophilus require the Fab and Fc regions to be separated by at least ten (or in the case of N. gonorrhoeae type I protease, nine) amino acids between Val222 and Cys241 (IgA1 numbering) for efficient access and cleavage. By contrast, the streptococcal IgA1 metalloproteinases require 12 or more appropriate amino acids between the Fab and Fc to maintain a minimum critical distance between the scissile bond and the start of the Fc.

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“…The IgA1 proteases of these pathogens are thought to be important virulence factors because they are produced in vivo (5,16,31), because convalescing patients have neutralizing antibodies to them (7,10,12), and because the three principal causes of bacterial meningitis, though genetically distinct, all produce an IgA1 protease (21,30). However, because the substrate of IgA1 proteases is restricted almost exclusively (4,41) to IgA1 from only humans, gorillas, chimpanzees, and orangutans (37), a convenient animal model is not available, and therefore, it is difficult to assess the contribution of IgA1 protease production to virulence.…”

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Amino Acid Sequence Requirements in the Hinge of Human Immunoglobulin A1 (IgA1) for Cleavage by Streptococcal IgA1 Proteases

et al. 2003

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The amino acid sequence requirements in the hinge of human immunoglobulin A1 (IgA1) for cleavage by IgA1 proteases of different species of Streptococcus were investigated. Recombinant IgA1 antibodies were generated with point mutations at proline 227 and threonine 228, the residues lying on either side of the peptide bond at which all streptococcal IgA1 proteases cleave wild-type human IgA1. The amino acid substitutions produced no major effect upon the structure of the mutant IgA1 antibodies or their functional ability to bind to Fc␣ receptors. However, the substitutions had a substantial effect upon sensitivity to cleavage with some streptococcal IgA1 proteases, with, in some cases, a single point mutation rendering the antibody resistant to a particular IgA1 protease. This effect was least marked with the IgA1 protease from Streptococcus pneumoniae, which showed no absolute requirement for either proline or threonine at residues 227 to 228. By contrast, the IgA1 proteases of Streptococcus oralis, Streptococcus sanguis, and Streptococcus mitis had an absolute requirement for proline at 227 but not for threonine at 228, which could be replaced by valine. There was evidence in S. mitis that proteases from different strains may have different amino acid requirements for cleavage. Remarkably, some streptococcal proteases appeared able to cleave the hinge at a distant alternative site if substitution prevented efficient cleavage of the original site. Hence, this study has identified key residues required for the recognition of the IgA1 hinge as a substrate by streptococcal IgA1 proteases, and it marks a preliminary step towards development of specific enzyme inhibitors.

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Cleavage of the Hormone Human Chorionic Gonadotropin, by the Type 1 IgA1 Protease ofNeisseria gonorrhoeae,and Its Implications

Cited by 21 publications

References 15 publications

Sites in the CH3 Domain of Human IgA1 That Influence Sensitivity to Bacterial IgA1 Proteases

Sites in the CH3 Domain of Human IgA1 That Influence Sensitivity to Bacterial IgA1 Proteases

The Influences of Hinge Length and Composition on the Susceptibility of Human IgA to Cleavage by Diverse Bacterial IgA1 Proteases

Amino Acid Sequence Requirements in the Hinge of Human Immunoglobulin A1 (IgA1) for Cleavage by Streptococcal IgA1 Proteases

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