The Consensus Binding Site on Fc

Superposition of the binding site footprints of the four natural IgG-Fc binding domains reveals the presence of a common surface patch on the Fc surface (Fig. 3a). Just six side chains are involved in forming this saddle-shaped consensus site between the 250's loop of the CH2 domain and the 430's loop of the CH3 domain. Together these side chains b

Figure 3 Superposition of the binding site footprints on IgG-Fc for the natural Fc binding proteins (a). Surface atoms are colored red, yellow, light blue, and dark blue, reflecting their participation in four, three, two, or one of these protein interfaces, respectively. Atoms in residues 252 to 254 and 434 to 436 form a nearly contiguous patch of the Fc surface that is common to all of the crystallographically characterized interactions. The crystal structure of an Fc-binding peptide (white) is shown in (b), and atoms in the solvent-protected footprint of the peptide are shown in (c). The peptide covers the same consensus set of atoms as the natural binding domains. (Adapted from DeLano et al., Science, 287, 1279-1283, 2000. With permission.)

Figure 3 Superposition of the binding site footprints on IgG-Fc for the natural Fc binding proteins (a). Surface atoms are colored red, yellow, light blue, and dark blue, reflecting their participation in four, three, two, or one of these protein interfaces, respectively. Atoms in residues 252 to 254 and 434 to 436 form a nearly contiguous patch of the Fc surface that is common to all of the crystallographically characterized interactions. The crystal structure of an Fc-binding peptide (white) is shown in (b), and atoms in the solvent-protected footprint of the peptide are shown in (c). The peptide covers the same consensus set of atoms as the natural binding domains. (Adapted from DeLano et al., Science, 287, 1279-1283, 2000. With permission.)

account for a contiguous surface patch of approximately 500 A2.

What is the driving force that has led nature to target this binding site repeatedly with so many diverse molecules? A trivial explanation would be that an important biological function of IgG, such as binding of the neonatal Fc receptor, is innately coupled to these residues. If disruption of this particular function is somehow beneficial to bacterial infection, then this hypothesis would explain why protein A and protein G binding domains have co-evolved to bind this site; however, it would not explain why rheumatoid factors are also specifically attracted to the hinge region.

An alternative hypothesis is that the innate physiochemi-cal composition of this site is inherently "sticky" and promotes binding as well as antigenicity. If the biological role for protein A and G is primarly to localize IgGs to the bacterial surface, perhaps to evade immune system surveillance, then it might simply be the case that the CH2/CH3 hinge region was the most evolutionarily efficient IgG surface to target for binding. Likewise, if this region is an innately attractive part of the protein surface, then that would explain the frequent emergence of autoimmune rheumatoid factors targeting Fc. We chose to evaluate this hypothesis by evolving novel IgG-Fc binding domains in the laboratory to discover if molecules selected purely for binding would indeed target the CH2/CH3 hinge region.

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