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* Laboratory for Immunology and Inflammation, Instituto di Ricerca e Cura a Carattere Scientifico Istituto Clinico Humanitas, Rozzano, Italy;
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland;
Division of Immunology, Helsinki University Central Hospital Laboratories Helsinki University Central Hospital Laboratory, Helsinki, Finland;
Mario Negri Institute, Milan, Italy; and
¶ Institute of General Pathology, University of Milan, Milan, Italy
The long pentraxin PTX3 is a multifunctional soluble molecule involved in inflammation and innate immunity. As an acute phase protein, PTX3 binds to the classical pathway complement protein C1q, limits tissue damage in inflammatory conditions by regulating apoptotic cell clearance, and plays a role in the phagocytosis of selected pathogens. This study was designed to investigate the interaction of PTX3 with factor H (FH), the main soluble alternative pathway regulatory protein. We report that PTX3 binds FH with an apparent Kd of 1.1 x 10–7 M, and define two binding sites for PTX3 on FH. The primary binding site is located on FH domains 19–20, which interact with the N-terminal domain of PTX3, while a secondary binding site on domain 7 binds the glycosylated PTX3 pentraxin domain. The FH Y402H polymorphism, which affects binding to the short pentraxin CRP, did not affect binding to PTX3. Surface-bound PTX3 enhances FH recruitment and iC3b deposition and PTX3-bound FH retains its activity as a cofactor for factor I-mediated C3b cleavage. Thus, our findings identify PTX3 as a unique FH ligand in that it can bind both of the two hot-spots of FH, namely SCR7 and SCR19–20 and indicate that PTX3 participates in the localization of functionally active FH.
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 work was supported by The Academy of Finland, the Sigrid Jusélius Foundation, Helsinki University Central Hospital Funds, and NIH EY11515 (to S.M.). This work is supported in part by funding under the European Commission (contracts: LSHM-CT-2004-512040: EMBIC; LSHG-CT-2005-005203: MUGEN; LSHP-CT-2003-503240: MUVAPRED), Telethon (Grant GGP05095), CARIPLO Foundation (NOBEL project), Ministero Università e Ricerca (MUR, application number 6669), and the University of Milan (FIRST project). The support of the Fondazione Humanitas per la Ricerca and Italian Association for Cancer Research is gratefully acknowledged. LD was supported by the International Graduate School in Molecular Medicine (Vita-Salute San Raffaele University, Italy) institutional fellowship.
2 Address correspondence and reprint requests to Dr. Livija Deban, Laboratory for Immunology and Inflammation, Instituto di Ricerca e Cura a Carattere Scientifico Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Italy. E-mail address: livija.deban{at}humanitas.it
3 Abbreviations used in this paper: CRP, C-reactive protein; FH, factor H; pAb, polyclonal Ab; SCR, short consensus repeat; NHS, normal human serum; AMD, age-related macular degeneration.
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