Optimal ligand discrimination by asymmetric dimerization and turnover of interferon receptors

In multicellular organisms, antiviral defense mechanisms evoke a reliable collective immune response despite the noisy nature of biochemical communication between tissue cells. A molecular hub of this response, the interferon I receptor (IFNAR), discriminates between ligand types by their affinity regardless of concentra-tion. To understand how ligand type can be decoded robustly by a single receptor, we frame ligand discrimination as an information-theoretic problem and systematically compare the major classes of receptor architectures: allosteric, homodimerizing, and het-erodimerizing. We demonstrate that asymmetric heterodimers achieve the best discrimination power over the entire physio-logical range of local ligand concentrations. This design enables sensing of ligand presence and type, and it buffers against mod-erate concentration fluctuations. In addition, receptor turnover, which drives the receptor system out of thermodynamic equi-librium, allows alignment of activation points for ligands of different affinities and thereby makes ligand discrimination prac-tically independent of concentration. IFNAR exhibits this optimal architecture, and our findings thus suggest that this special-ized receptor can robustly decode digital messages carried by its different ligands.