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    Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46)

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    Author
    Giannakis, E; Jokiranta, TS; Ormsby, RJ; Duthy, TG; Male, DA; Christiansen, D; Fischetti, VA; Bagley, C; Loveland, BE; Gordon, DL
    Date
    2002-05-01
    Source Title
    JOURNAL OF IMMUNOLOGY
    Publisher
    AMER ASSOC IMMUNOLOGISTS
    University of Melbourne Author/s
    Christiansen, Dale; LOVELAND, BRUCE
    Affiliation
    Pathology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Giannakis, E., Jokiranta, T. S., Ormsby, R. J., Duthy, T. G., Male, D. A., Christiansen, D., Fischetti, V. A., Bagley, C., Loveland, B. E. & Gordon, D. L. (2002). Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46). JOURNAL OF IMMUNOLOGY, 168 (9), pp.4585-4592. https://doi.org/10.4049/jimmunol.168.9.4585.
    Access Status
    This item is currently not available from this repository
    URI
    http://hdl.handle.net/11343/26246
    DOI
    10.4049/jimmunol.168.9.4585
    Description

    C1 - Journal Articles Refereed

    Abstract
    Adherence of group A streptococcus (GAS) to keratinocytes is mediated by an interaction between human CD46 (membrane cofactor protein) with streptococcal cell surface M protein. CD46 belongs to a family of proteins that contain structurally related short consensus repeat (SCR) domains and regulate the activation of the complement components C3b and/or C4b. CD46 possesses four SCR domains and the aim of this study was to characterize their interaction with M protein. Following confirmation of the M6 protein-dependent interaction between GAS and human keratinocytes, we demonstrated that M6 protein binds soluble recombinant CD46 protein and to a CD46 construct containing only SCRs 3 and 4. M6 protein did not bind to soluble recombinant CD46 chimeric proteins that had the third and/or fourth SCR domains replaced with the corresponding domains from another complement regulator, CD55 (decay-accelerating factor). Homology-based molecular modeling of CD46 SCRs 3 and 4 revealed a cluster of positively charged residues between the interface of these SCR domains similar to the verified M protein binding sites on the plasma complement regulators factor H and C4b-binding protein. The presence of excess M6 protein did not inhibit the cofactor activity of CD46 and the presence of excess C3b did not inhibit the ability of CD46 to bind M6 protein by ELISA. In conclusion, 1) adherence of M6 GAS to keratinocytes is M protein dependent and 2) a major M protein binding site is located within SCRs 3 and 4, probably at the interface of these two domains, at a site distinct from the C3b-binding and cofactor site of CD46.
    Keywords
    Immunology not elsewhere classified; Immune System and Allergy

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