Paired receptors

Paired receptors are pairs or clusters of receptor proteins that bind to extracellular ligands but have opposing activating and inhibitory signaling effects. Traditionally, paired receptors are defined as homologous pairs with similar extracellular domains and different cytoplasmic regions, whose genes are located together in the genome as part of the same gene cluster and which evolved through gene duplication. Homologous paired receptors often, but not always, have a shared ligand in common. More broadly, pairs of receptors have been identified that exhibit paired functional behavior - responding to a shared ligand with opposing intracellular signals - but are not closely homologous or co-located in the genome. Paired receptors are highly expressed in the cells of the immune system, especially natural killer (NK) and myeloid cells, and are involved in immune regulation.

Structure

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).

Genetics and evolution Homologous paired receptors are located in the same gene cluster and are thought to have evolved through gene duplication. Sequence features such as the presence of an ITIM-like sequence in the 3' untranslated region of some activating receptors imply that the activating members of the pair likely evolved from the inhibitory members. A number of pathogens interact with the inhibitory member of a pair as a means of immune evasion or viral entry, suggesting that activating members with similar binding competencies may be an evolutionary response to this mechanism. This hypothesis is known as the "counterbalance theory" and these evolutionary dynamics represent an evolutionary arms race between pathogens and the host immune system. The evolutionary pressures on some paired-receptor families have been described as examples of the "Red Queen" effect. Including non-paired examples, over 300 potential immune inhibitory receptors have been identified in the human genome. There are strong indications that paired receptors are rapidly and recently evolving. These genetic regions have high levels of gene polymorphism, and the gene repertoires found in the genomes of closely related lineages vary significantly. The selective pressure experienced by the host from pathogens is thought to underlie this rapid evolution. Although paired receptors are best characterized as part of the human and mouse immune systems, they have also been studied in other organisms. The chicken (Gallus gallus domesticus) genome contains a number of examples including a very large family, the chicken Ig-like receptors (CHIR) with over 100 members. Paired receptor evolution has also been studied in Xenopus (clawed frog) species. The adaptive immune system is unique to jawed vertebrates, but an example of a paired receptor family has been identified in a jawless vertebrate, termed agnathan paired receptors resembling Ag receptors (APAR) in the hagfish.

Expression Expression of paired receptors is common in many types of leukocytes, especially myeloid cells and natural killer (NK) cells. Activation of NK cells is a complex regulatory process modulated by a number of different paired receptor families coexpressed in this cell type. In some cases, only one member of the pair is expressed in a cell type. Expression of the paired members in a single cell type may vary with time, or the proteins may differ in subcellular localization, resulting in variations in signaling. Expression in NK cells can be stochastic, resulting in unique variations in receptor repertoire. Some paired receptors are expressed outside the immune system, for example in neurons, endothelium, and epithelium but in many examples, wide tissue distribution can be observed.

Function

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