Paired receptors are membrane proteins with extracellular domains that interact with extracellular ligands. The extracellular region may contain multiple repeating protein domains and may be members of either the immunoglobulin or C-type lectin families. The extracellular domains of homologous paired receptors are typically very similar in sequence but have different binding affinity for their shared ligands, with the inhibitory member of the pair binding more tightly.
Homologous paired receptors have characteristic differences in their transmembrane and cytoplasmic regions that distinguish the activating and inhibiting members of the pair. Inhibitory receptors have a cytoplasmic sequence typically containing at least one immunoreceptor tyrosine-based inhibitory motif (ITIM). Activating receptors have a truncated cytoplasmic sequence compared to their corresponding inhibitory receptor and feature a positively charged amino acid residue in their transmembrane domain, enabling protein-protein interaction with an adaptor protein that possesses a immunoreceptor tyrosine-based activation motif (ITAM).