The binding site for C1q on IgG

Abstract

In humoral defence, pathogens are cleared by antibodies acting as adaptor molecules: they bind to antigen and trigger clearance mechanisms such as phagocytosis, antibody-dependent cell-mediated cytotoxicity and complement lysis. The first step in the complement cascade is the binding of C1q to the antibody. There are six heads on C1q, connected by collagen-like stems to a central stalk, and the isolated heads bind to the Fc portion of antibody rather weakly, with an affinity of 100 microM (ref. 3). Binding of antibody to multiple epitopes on an antigenic surface, aggregates the antibody and this facilitates the binding of several C1q heads, leading to an enhanced affinity of about 10 nM (ref. 1). Within the Fc portion of the antibody, C1q binds to the CH2 domain. The interaction is sensitive to ionic strength, and appears to be highly conserved throughout evolution as C1q reacts with IgG from different species (for example see ref. 8). By systematically altering surface residues in the mouse IgG2b isotype, we have localized the binding site for C1q to three side chains, Glu 318, Lys 320 and Lys 322. These residues are relatively conserved in other antibody isotypes, and a peptide mimic of this sequence is able to inhibit complement lysis. We propose that this sequence motif forms a common core in the interactions of IgG and C1q.

Pathophysiological Roles of Calreticulin in Autoimmune Disease

“…This competition implies that calreticulin and immunoglobulins may have similar binding sites recognized by C1q. A major C1q-binding site on IgG is the highly species conserved CH2 domain in the Fc portion of the molecule, which is ExKxK (at positions 318, 320 and 322) [72]. A synthetic peptide of this sequence was shown to inhibit complement lysis.…”

Mutations within a human IgG2 antibody form distinct and homogeneous disulfide isomers but do not affect Fc gamma receptor or C1q binding

“…2 Thus, studies that attempt to explain this disparity have focused on the hinge region, where the sequence variation is highest. 2,[4][5][6][7][8][9][10][11][12][13][14] The unique lower hinge residues from an IgG2 have been placed into both an IgG1 and IgG3 antibody background 4,11,12,15 and assayed for binding to Fc receptors. The IgG1 mutant showed reduced binding to all tested Fc gamma receptors, however, the reduction observed was well below that of the wild-type IgG2/Fc receptors affinities.…”

The Classical and Regulatory Functions of C1q in Immunity and Autoimmunity

“…It can be activated through 3 different pathways, i.e., the classical, lectin and alternative pathways (1,2). The classical pathway is mainly elicited by immune complexesinvolving binding of C1q, which forms a pentameric complex with the C1r 2 C1s 2 serine protease tetramer, to the Fc regions of antibodies (1,3). Complement is also activated by other C1q ligands besides immune complexes.…”