Binding of the long pentraxin PTX3 to factor H: Interacting domains and function in the regulation of complement activation

Livija Deban, Hanna Jarva, Markus J. Lehtinen, Barbara Bottazzi, Antonio Bastone, Andrea Doni, T. Sakari Jokiranta, Alberto Mantovani, Seppo Meri

Research output: Contribution to journalArticlepeer-review

Abstract

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 × 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.

Original languageEnglish
Pages (from-to)8433-8440
Number of pages8
JournalJournal of Immunology
Volume181
Issue number12
Publication statusPublished - Dec 15 2008

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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