Binding of the long pentraxin PTX3 to factor H: interacting domains and function in the regulation of complement activation.
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.
Deban
Livija
L
Laboratory for Immunology and Inflammation, Instituto di Ricerca e Cura a Carattere Scientifico Istituto Clinico Humanitas, Rozzano, Italy. livija.deban@humanitas.it
Jarva
Hanna
H
Lehtinen
Markus J
MJ
Bottazzi
Barbara
B
Bastone
Antonio
A
Doni
Andrea
A
Jokiranta
T Sakari
TS
Mantovani
Alberto
A
Meri
Seppo
S
D000209:Acute-Phase Proteins / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D002097:C-Reactive Protein / Q000378:metabolism* / Q000502:physiology; D016466:CHO Cells; D017242:Complement Factor H / Q000378:metabolism / Q000502:physiology; D003170:Complement Pathway, Alternative / Q000276:immunology*; D016384:Consensus Sequence; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D019169:Jurkat Cells; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D000683:Serum Amyloid P-Component / Q000378:metabolism* / Q000502:physiology; D000099153:Pentraxins
D000209:Acute-Phase Proteins; D002097:C-Reactive Protein; D017242:Complement Factor H; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C493495:CFH protein, human