Article

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

Laboratory for Immunology and Inflammation, Instituto di Ricerca e Cura a Carattere Scientifico Istituto Clinico Humanitas, Rozzano, Italy.
The Journal of Immunology (impact factor: 5.79). 01/2009; 181(12):8433-40.
Source: PubMed

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 K(d) 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.

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Keywords

acute phase protein
 
classical pathway
 
domain 7 binds
 
factor H
 
factor I-mediated C3b cleavage
 
FH Y402H polymorphism
 
functionally active FH
 
glycosylated PTX3 pentraxin domain
 
iC3b deposition
 
inflammatory conditions
 
limits tissue damage
 
pentraxin PTX3
 
PTX3 binds
 
PTX3 binds FH
 
PTX3-bound FH
 
regulating apoptotic cell clearance
 
secondary binding site
 
short pentraxin CRP
 
Surface-bound PTX3 enhances FH recruitment
 
unique FH ligand