Paired receptors

domain of an NKG2 receptor. From . 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. 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. 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==

(blue) interacting with the MHC class I ligand HLA-Cw4 (red), an HLA-Cw4-specific peptide (yellow), and beta-2 microglobulin (green). From . Paired receptors transduce extracellular signals through opposing intracellular signaling pathways. Canonically, inhibitory receptors recruit phosphatases through their ITIM motifs, inhibiting the function of cells in which they are expressed. By contrast, activating receptors interact with adaptor proteins such as DAP-12 bearing an ITAM motif, which in turn recruit kinases such as Syk and ZAP70. Lipids such as phosphatidylethanolamine and phosphatidylserine, sugars and sialylated glycans, and nucleic acids can all serve as ligands for some paired receptors. The binding affinity of paired receptors' extracellular domains for their ligands is generally fairly weak, with dissociation constants (Kd) in the micromolar (μM) range. However, the inhibitory member of a pair usually binds with higher affinity than the activating member. This can produce a competitive inhibition effect, in which the inhibitory member of the pair out-competes its activating counterpart for ligand binding; other mechanisms of interference with activation, such as disrupting dimerization, have also been described. Thus the net baseline signal from the pair is usually inhibitory, but may be modulated through differences in expression, surface density, subcellular localization, or other factors. In NK cells, ligands for inhibitory receptors are often MHC class I (MHC-I) molecules, while those for activating receptors may include signals of abnormality or infection such as proteins from pathogens or tumors, or molecules associated with cell stress. Endogenous ligands for inhibitory receptors are better characterized than those for activating receptors. Paired receptor signaling may represent maintenance of homeostasis such that immune responses to normal host cells are inhibited, while responses to abnormal or pathogenic molecules in the environment are activating. NK activation in the absence of inhibitory receptor signals from endogenous ligands is a molecular mechanism for the missing-self hypothesis of NK activation. ==Interaction with pathogens==

A number of examples of molecular mimicry by pathogens, emulating natural endogenous ligands of paired receptors for immune evasion, have been described in the literature. Such interactions are particularly common with the inhibitory members of receptor pairs, bolstering the hypothesis that activating partners are a later evolutionary response to this immune escape strategy. The first described interaction between a paired receptor and a viral protein identified ILT-2 and ILR-4 (LILRB1 and LILRB2) as targets for herpes simplex virus UL18 protein, which resembles an MHC-I molecule. Variations in susceptibility to mouse cytomegalovirus infection due to differences in Ly49-family paired receptors among mouse strains are well-characterized, and are attributed to the structural resemblance between the viral protein m157 and MHC-I molecules. The pathogenic bacterium Escherichia coli K1 exposes surface polysialic acid molecules that serve as a molecular mimic for the native ligand of the inhibitory receptor Siglec-11, but induces an opposing response through interactions with the paired activating receptor Siglec-16, exemplifying the benefit of activating receptors as defense mechanisms against molecular mimicry by pathogens. Paired receptors are also used as viral entry receptors by a number of viruses and occasionally as entry mechanisms for other pathogens. Sialylation is common among mammalian cell-surface proteins and a number of pathogens use sialic acid - either self-synthesized or obtained from the host cell - to evade host immunity, including by interacting with inhibitory siglec receptors. ==Families==

There are two main groups of paired receptors, distinguished by extracellular regions containing immunoglobulin or C-type lectin domains. Nomenclature within these families is complex and has changed over time as new members were identified. In general, the example of the LILR family applies; genes designated A represent the inhibitory receptor and genes designated B represent the activating receptor. This family has undergone significant diversification in primate lineages. • The leukocyte immunoglobulin-like receptors (LILR) family contains 13 genes, including two pseudogenes. They have 2-4 Ig domains. One member, LILRA3, lacks a transmembrane region and is a soluble protein; others may be expressed in soluble form through alternative splicing. Like the similar KIR family, LILR genes are found in the LRC and are polymorphic, though less so than KIR. LILR proteins are broadly expressed in immune cells and have very diverse ligands. with the more distantly related SIRPD and SIRPB2 not yet well characterized. SIRPA interacts with CD47, a regulator of phagocytosis. They are expressed broadly, especially in endothelium and epithelium They have been extensively studied for their role in cancer and have been used as cancer biomarkers. These proteins bind sialic acids, and are often targeted by pathogens. • NKR-P1 (CD161) is a member of a paired receptor group in rodents, but the human genome contains only one, inhibitory receptor, NKRP1A (KLRB1). • The Ly49 family in mice has been extensively studied for its role in NK activation using laboratory mice as a model organism, but has no homologous gene cluster in the human genome. The KIR family is the functional equivalent. ==References==