Factor H (FH)-related protein 1 (FHR-1) is one
of the five human factor H-related proteins,
which share sequence and structural homology
with the alternative pathway complement
inhibitor FH. Genetic studies on
disease associations and functional analyses indicate that
FHR-1 enhances complement activation by co
mpetitive inhibition of FH binding to some
surfaces and immune proteins. We have recen
tly shown that FHR-1 binds to pentraxin 3.
Here, our aim was to investigate whether FH
R-1 binds to another
pentraxin, C-reactive
protein (CRP), analyze the functional relevance
of this interaction and study the role of FHR-
1 in complement activation and regulation. FHR-
1 did not bind to native,
pentameric CRP but
it bound strongly to monomeric CRP via its C-term
inal domains. FHR-1 at high concentration
competed with FH for CRP binding, indicating
possible complement de
-regulation also on
this ligand. FHR-1 did not inhibi
t regulation of solid phase C3 convertase by FH and did not
inhibit terminal complement complex forma
tion induced by zymosan. On the contrary, by
binding C3b, FHR-1 allowed C3 convertase form
ation and thereby enhanced complement
activation. FHR-1/CRP interacti
ons increased complement activ
ation via the classical and
alternative pathways on surfaces such as th
e extracellular matrix and necrotic cells.
Altogether, these results identify CRP as a lig
and for FHR-1 and suggest
that FHR-1 enhances
rather than inhibits complement activation, wh
ich may explain the protective effect of FHR-1
deficiency in age-related macular degeneration
