Interaction of C1q with IgG1, C-reactive protein and pentraxin 3: mutational studies using recombinant globular head modules of human C1q A, B, and C chains.
C1q is the first subcomponent of the classical complement pathway that can interact with a range of biochemically and structurally diverse self and nonself ligands. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has specific and differential binding properties toward C1q ligands. It is largely considered that C1q-ligand interactions are ionic in nature; however, the complementary ligand-binding sites on C1q and the mechanisms of interactions are still unclear. To identify the residues on the gC1q domain that are likely to be involved in ligand recognition, we have generated a number of substitution mutants of ghA, ghB, and ghC modules and examined their interactions with three selected ligands: IgG1, C-reactive protein (CRP), and pentraxin 3 (PTX3). Our results suggest that charged residues belonging to the apex of the gC1q heterotrimer (with participation of all three chains) as well as the side of the ghB are crucial for C1q binding to these ligands, and their contribution to each interaction is different. It is likely that a set of charged residues from the gC1q surface participate via different ionic and hydrogen bonds with corresponding residues from the ligand, instead of forming separate binding sites. Thus, a recently proposed model suggesting the rotation of the gC1q domain upon ligand recognition may be extended to C1q interaction with CRP and PTX3 in addition to IgG1.
Department of Biochemistry, Sofia University, St. Kliment Ohridski, 8 Dragan Tsankov Street, Sofia 1164, Bulgaria.
Lubka T
LT
Roumenina
Marieta M
MM
Ruseva
Alexandra
A
Zlatarova
Rohit
R
Ghai
Martin
M
Kolev
Neli
N
Olova
Mihaela
M
Gadjeva
Alok
A
Agrawal
Barbara
B
Bottazzi
Alberto
A
Mantovani
Kenneth B M
KB
Reid
Uday
U
Kishore
Mihaela S
MS
Kojouharova
D000595:Amino Acid Sequence; D002097:C-Reactive Protein / Q000378:metabolism*; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007074:Immunoglobulin G / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009994:Osmolar Concentration; D017354:Point Mutation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D007074:Immunoglobulin G; D021122:Protein Subunits; D011994:Recombinant Proteins; D015922:Complement C1q; D002097:C-Reactive Protein; D019362:Cytochrome P-450 CYP2B1