Isotypes of IgG: Comparison of the primary structures of three pairs of isotypes which differ in their ability to activate complement

Abstract

The comparison of three pairs of isotypic Cγ‡ primary structures is made with reference to the known crystallographic structure of Fab and Fc from human IgGl. Contiguous residue positions are assigned to sub-regions based on their occurrence in secondary structures, extended chains or the loops which connect them, in the crystallographic models. Simple inspection reveals that residue positions having identical amino acids in all six Cγ are found mainly in extended chain sub-regions forming parts of β-sheets. However, average structural dissimilarity (ASD) values in loops which mediate V H to Cγl and Cγ2-Cγ3 interactions are as low as those obtained for extended chain subregions, implying that these structures are conserved among IgGs. In contrast, loop structures which are candidates for Cγl-Cγ2 interactions show high values of ASD, indicating little structural homology is conserved. Longitudinal Fab-Fc interactions, if they occur at all, probably occur via remarkably different residue contacts in different IgGs. Our analysis yields no clear-cut evidence for a pathway by which isotypic IgGs diverged in biologic effector functions. Great variation in primary structure is seen in the ‘hinge’ region, and in some loop and extended chain subregions exposed to solvent in the Cγ2 Cγ2 domain. These variations may account for the ability or inability of the six IgGs compared to interact with the first component of complement (C1) since some structural features in those regions are shared among those Fcs which bind C1. We speculate that the C1. binding site is determined by the extended chain formed by residues Lys-290 to Glu-295 of human IgGl heavy chain.