Abstract
Complement factor H-related protein 1 (CFHR1) is a complement regulator which has been reported to regulate complement by blocking C5 convertase activity and interfering with C5b surface association. CFHR1 also competes with complement factor H (CFH) for binding to C3b, and may act as an antagonist of CFH-directed regulation on cell surfaces. We have employed site-directed mutagenesis in conjunction with ELISA-based and functional assays to isolate the binding interaction that CFHR1 undertakes with complement components C3b and C3d to a single shared interface. The C3b/C3d:CFHR1 interface is identical to that which occurs between the two C-terminal domains (SCR19-20) of CFH and C3b. Moreover, we have been able to corroborate that dimerization of CFHR1 is necessary for this molecule to bind effectively to C3b and C3d, or compete with CFH. Finally, we have established that CFHR1 competes with complement factor H-like protein 1 (CFHL-1) for binding to C3b. CFHL-1 is a CFH gene splice variant, which is almost identical to the N-terminal 7 domains of CFH (SCR1-7). CFHR1, therefore, not only competes with the C-terminus of CFH for binding to C3b, but also sterically blocks the interaction that the N-terminus of CFH undertakes with C3b, and which is required for CFH-regulation.
Highlights
The proteins encoded by the complement factor H (CFH) gene family include the complement regulator CFH as well as five CFH-related proteins, Complement factor H-related protein 1 (CFHR1), CFHR2, CFHR3, CFHR4 and CFHR5
A separate putative C3d interaction site has been identified within SCR20 of CFH [6]
With regards to the C-terminal CFH:C3b TED binding site, two independently derived three-dimensional structures of wild-type and mutant forms of CFH SCR19-20 in complex with C3d have been reported, which delineate essentially the same interface, and which is widely accepted as being reflective of the physiologic CFH:C3b TED interaction
Summary
The proteins encoded by the CFH gene family include the complement regulator CFH as well as five CFH-related proteins, CFHR1, CFHR2, CFHR3, CFHR4 and CFHR5. All of these molecules are composed exclusively of compact repeating domains, each of about 60 residues, known as short consensus repeats (SCRs) or complement control protein modules (CCPs) [1, 2]. Human CFH is a 150 kDa plasma protein that is comprised of twenty SCR modules, which is found in circulation at concentrations ranging from ~0.8–3.8 μM (116–562 μg/ml) [3]. Alternative splicing of the CFH gene results in the production of a truncated 42 kDa isoform of CFH known as complement factor H-like protein 1 (CFHL-1). With regards to the CFHR proteins, each of which are encoded by unique
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