Affimer proteins inhibit immune complex binding to Fc?RIIIa with high specificity through competitive and allosteric modes of action.

ABSTRACT: Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (Fc?Rs). High sequence identity (98%) between the genes encoding Fc?RIIIa (expressed on macrophages and natural killer cells) and Fc?RIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of Fc?RIIIa-specific artificial binding proteins called "Affimer" that block IgG binding and abrogate Fc?RIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically.

SUBMITTER: Robinson JI 

PROVIDER: S-EPMC5776790 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature