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* Department of Laboratory Medicine, Medical Protein Chemistry, University of Lund, Malmö, Sweden;
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and
University of Paris, Paris, France
Neisseria gonorrhoeae, the causative agent of gonorrhea, is a natural infection only in humans. The resistance of N. gonorrhoeae to normal human serum killing correlates with porin (Por)-mediated binding to the complement inhibitor, C4b-binding protein (C4BP). The entire binding site for both porin molecules resides within complement control protein domain 1 (CCP1) of C4BP. Only human and chimpanzee C4BPs bind to Por1B-bearing gonococci, whereas only human C4BP binds to Por1A strains. We have now used these species-specific differences in C4BP binding to gonococci to map the porin binding sites on CCP1 of C4BP. A comparison between human and chimpanzee or rhesus C4BP CCP1 revealed differences at 4 and 12 amino acid positions, respectively. These amino acids were targeted in the construction of 13 recombinant human mutant C4BPs. Overall, amino acids T43, T45, and K24 individually and A12, M14, R22, and L34 together were important for binding to Por1A strains. Altering D15 (found in man) to N15 (found in rhesus) introduced a glycosylation site that blocked binding to Por1A gonococci. C4BP binding to Por1B strains required K24 and was partially shielded by additional glycosylation in the D15N mutant. Only those recombinant mutant C4BPs that bound to bacteria rescued them from 100% killing by rhesus serum, thereby providing a functional correlate for the binding studies and highlighting C4BP function in gonococcal serum resistance.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, and the Foundations of Kock, Österlund, King Gustav V’s 80th anniversary, and a research grant from the University Hospital in Malmö (all to A.M.B.); the Finnish Cultural Foundation and the Maud Kuistila Foundation (to H.J.); and the National Institutes of Health/National Institutes of Allergy and Infectious Diseases Grants AI 054544 (to S.R.) and AI 032725 (to P.A.R.).
2 Current address: Department of Bacteriology and Immunology, Haartman Institute and Helsinki University Central Hospital, Helsinki, Finland.
3 Address correspondence and reprint requests to Dr. Anna Blom, Lund University; Department of Laboratory Medicine, Division of Medical Protein Chemistry, University Hospital Malmö, Entrance 46, The Wallenberg Laboratory, Malmö, Sweden. E-mail address: Anna.Blom{at}med.lu.se
4 Abbreviations used in this paper: DGI, disseminated gonococcal infection; C4BP, C4b-binding protein; CCP, complement control protein (domain); NGF, N-glycosidase F; NHS, normal human serum; Por, porin; PVDF, polyvinylidene difluoride; wt, wild type.
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