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Paired receptors are pairs or clusters of
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s that
bind BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name Daemon (computing), daemon''), performs both of the main DNS server roles, acting ...
to extracellular
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
s but have opposing activating and inhibitory
signaling A signal is both the process and the result of transmission of data over some media accomplished by embedding some variation. Signals are important in multiple subject fields including signal processing, information theory and biology. ...
effects. Traditionally, paired receptors are defined as homologous pairs with similar
extracellular domain An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A notabl ...
s and different
cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...
regions, whose
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s are located together in the
genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
as part of the same
gene cluster A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides or proteins which collectively share a generalized function and are often located within a few thousand base pairs of each othe ...
and which evolved through
gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...
. 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 The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
, especially
natural killer Nature is an inherent character or constitution, particularly of the ecosphere or the universe as a whole. In this general sense nature refers to the laws, elements and phenomena of the physical world, including life. Although humans are par ...
(NK) and
myeloid cell Myeloid tissue, in the bone marrow sense of the word ''wikt:myeloid#Adjective, myeloid'' (''wikt:myelo-#Prefix, myelo-'' + ''wikt:-oid#Suffix, -oid''), is tissue (biology), tissue of bone marrow, of bone marrow cell lineage, or resembling bon ...
s, and are involved in immune regulation.


Structure

Paired receptors are
membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
s with
extracellular domain An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A notabl ...
s that interact with extracellular ligands. The extracellular region may contain multiple repeating
protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
s and may be members of either the
immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
or
C-type lectin A C-type lectin (CLEC) is a type of carbohydrate-binding protein known as a lectin. The C-type designation is from their requirement for calcium for binding. Proteins that contain C-type lectin domains have a diverse range of functions including c ...
families. The extracellular domains of homologous paired receptors are typically very similar in sequence but have different
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
for their shared ligands, with the inhibitory member of the pair binding more tightly. Homologous paired receptors have characteristic differences in their
transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
and
cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...
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 An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family fou ...
(ITIM). Activating receptors have a truncated cytoplasmic sequence compared to their corresponding inhibitory receptor and feature a positively charged
amino acid residue In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
in their transmembrane domain, enabling protein-protein interaction with an adaptor protein that possesses a
immunoreceptor tyrosine-based activation motif An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors, cell-surface proteins found mainly on immune ce ...
(ITAM).


Genetics and evolution

Homologous paired receptors are located in the same
gene cluster A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides or proteins which collectively share a generalized function and are often located within a few thousand base pairs of each othe ...
and are thought to have evolved through
gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...
. Sequence features such as the presence of an ITIM-like sequence in the
3' untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
of some activating receptors imply that the activating members of the pair likely evolved from the inhibitory members. A number of
pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
s interact with the inhibitory member of a pair as a means of
immune evasion Antigenic escape, immune escape, immune evasion or escape mutation occurs when the immune system of a host, especially of a human being, is unable to respond to an infectious agent: the host's immune system is no longer able to recognize and elimi ...
or
viral entry Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell (biology), cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Desp ...
, 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 In evolutionary biology, an evolutionary arms race is an ongoing struggle between competing sets of co-evolving genes, phenotypic and behavioral traits that develop escalating adaptations and counter-adaptations against each other, resembling the ...
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 The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...
. There are strong indications that paired receptors are rapidly and recently evolving. These genetic regions have high levels of
gene polymorphism A gene is said to be polymorphic if more than one allele occupies that gene's Locus (genetics), locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of ...
, and the gene repertoires found in the genomes of closely related lineages vary significantly. The
selective pressure Evolutionary pressure, selective pressure or selection pressure is exerted by factors that reduce or increase reproductive success in a portion of a population, driving natural selection. It is a quantitative description of the amount of change oc ...
experienced by the host from
pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
s 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 The chicken (''Gallus gallus domesticus'') is a domesticated subspecies of the red junglefowl (''Gallus gallus''), originally native to Southeast Asia. It was first domesticated around 8,000 years ago and is now one of the most common and w ...
(''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 ''Xenopus'' () (Gk., ξενος, ''xenos'' = strange, πους, ''pous'' = foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described with ...
'' (clawed frog) species. The
adaptive immune system The adaptive immune system (AIS), also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The ac ...
is unique to
jawed vertebrates Gnathostomata (; from Ancient Greek: (') 'jaw' + (') 'mouth') are jawed vertebrates. Gnathostome diversity comprises roughly 60,000 species, which accounts for 99% of all extant vertebrates, including all living bony fishes (both ray-finned ...
, 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 Hagfish, of the Class (biology), class Myxini (also known as Hyperotreti) and Order (biology), order Myxiniformes , are eel-shaped Agnatha, jawless fish (occasionally called slime eels). Hagfish are the only known living Animal, animals that h ...
.


Expression

Expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Expression (mathematics), Symbolic description of a mathematical object * Fixed expression, a form of words with a specific meaning * Idiom, a type of ...
of paired receptors is common in many types of
leukocyte White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s, especially
myeloid cell Myeloid tissue, in the bone marrow sense of the word ''wikt:myeloid#Adjective, myeloid'' (''wikt:myelo-#Prefix, myelo-'' + ''wikt:-oid#Suffix, -oid''), is tissue (biology), tissue of bone marrow, of bone marrow cell lineage, or resembling bon ...
s and
natural killer Nature is an inherent character or constitution, particularly of the ecosphere or the universe as a whole. In this general sense nature refers to the laws, elements and phenomena of the physical world, including life. Although humans are par ...
(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 The cells of eukaryotic organisms are elaborately subdivided into functionally-distinct membrane-bound compartments. Some major constituents of eukaryotic cells are: extracellular space, plasma membrane, cytoplasm, nucleus, mitochondria, Golgi a ...
, resulting in variations in signaling. Expression in NK cells can be
stochastic Stochastic (; ) is the property of being well-described by a random probability distribution. ''Stochasticity'' and ''randomness'' are technically distinct concepts: the former refers to a modeling approach, while the latter describes phenomena; i ...
, resulting in unique variations in receptor repertoire. Some paired receptors are expressed outside the immune system, for example in
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s,
endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...
, and
epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
but in many examples, wide tissue distribution can be observed.


Function

Paired receptors transduce extracellular signals through opposing intracellular signaling pathways. Canonically, inhibitory receptors recruit
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s through their
ITIM ''Itim'' ( Filipino: ''Black''), released overseas as ''The Rites of May'', is a 1976 Philippine supernatural horror film directed by Mike de Leon in his feature film directorial debut, from a screenplay written by Clodualdo del Mundo Jr. a ...
motifs, inhibiting the function of cells in which they are expressed. By contrast, activating receptors interact with adaptor proteins such as
DAP-12 TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the ''TYROBP'' gene. Function This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation m ...
bearing an ITAM motif, which in turn recruit
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
s such as
Syk Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
and
ZAP70 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding ...
. Ligands for paired receptors can be very diverse. They are often proteins; the best-characterized are the
MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on ...
molecules, but a number of other endogenous molecules have been described as ligands for at least one family of paired receptors, and in a few cases in the LILR family, even intact bacteria or viruses can serve as ligands.
Lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
s such as
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...
and
phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via a ...
,
sugar Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecul ...
s and sialylated
glycan The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate ...
s, and
nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...
s can all serve as ligands for some paired receptors. The
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
of paired receptors' extracellular domains for their ligands is generally fairly weak, with
dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant (''K''D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex ...
s (Kd) in the
micromolar Molar concentration (also called molarity, amount concentration or substance concentration) is the number of moles of solute per liter of solution. Specifically, It is a measure of the concentration of a chemical species, in particular, of a s ...
(μM) range. However, the inhibitory member of a pair usually binds with higher affinity than the activating member. This can produce a
competitive inhibition Competitive inhibition is interruption of a chemistry, chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for molecular binding, binding or chemical bond, bonding. Any metabolism, metabolic or c ...
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
dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer ** TH-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * ...
ization, 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 class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on ...
(MHC-I) molecules, while those for activating receptors may include signals of abnormality or infection such as proteins from
pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
s or
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s, 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 In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
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 Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of sever ...
by pathogens, emulating natural endogenous ligands of paired receptors for
immune evasion Antigenic escape, immune escape, immune evasion or escape mutation occurs when the immune system of a host, especially of a human being, is unable to respond to an infectious agent: the host's immune system is no longer able to recognize and elimi ...
, 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 Leukocyte immunoglobulin-like receptor subfamily B member 1 is a protein that in humans is encoded by the ''LILRB1'' gene. Function This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene clu ...
and
LILRB2 Leukocyte immunoglobulin-like receptor subfamily B member 2 is a protein that in humans is encoded by the ''LILRB2'' gene. This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at ch ...
) as targets for
herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two members of the Herpesviridae#Human herpesvirus types, human ''Herpesviridae'' family, a set of viruses that produce Viral disease, viral infections in the majority of humans. Both HSV-1 a ...
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 ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
K1'' exposes surface
polysialic acid Polysialic acid is an unusual posttranslational modification that occurs on neural cell adhesion molecules (NCAM). Polysialic acid is considerably anionic. This strong negative charge gives this modification the ability to change the protein's surf ...
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 Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell (biology), cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Desp ...
receptors by a number of viruses and occasionally as entry mechanisms for other pathogens.
Sialylation Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" () was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is ''N''-acetylneuraminic acid (N ...
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 An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
or
C-type lectin A C-type lectin (CLEC) is a type of carbohydrate-binding protein known as a lectin. The C-type designation is from their requirement for calcium for binding. Proteins that contain C-type lectin domains have a diverse range of functions including c ...
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.


Immunoglobulin-like receptors

Immunoglobulin-like receptors are members of the
immunoglobulin superfamily The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...
and have one or more 70-110 residue
immunoglobulin domain The immunoglobulin domain, also known as the immunoglobulin fold, is a type of protein domain that consists of a 2-layer sandwich of 7-9 antiparallel β-strands arranged in two β-sheets with a Greek key topology, consisting of about 125 amino ...
s (Ig) in their extracellular region, typically multiple such domains in tandem. Many of the genes encoding these proteins occur in the
leukocyte receptor complex The leukocyte immunoglobulin-like receptors (LILR) are a family of receptors possessing extracellular immunoglobulin domains. They are also known as CD85, ILTs and LIR, and can exert immunomodulatory effects on a wide range of immune cells.Damian ...
(LRC), a large
gene cluster A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides or proteins which collectively share a generalized function and are often located within a few thousand base pairs of each othe ...
on human chromosome 19. Members of this group found in the
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...
include: * The
killer-cell immunoglobulin-like receptor Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. In humans, they are encoded in the leukocyte receptor c ...
(KIR) family contains proteins with 2-3 extracellular Ig domains and long (inhibitory) or short (activating) cytoplasmic regions. Typically expressed in NK and some
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s, they interact with
MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on ...
. This gene family located in the LRC is highly polymorphic and there is individual variation in both
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
s and copy number, as well as in
alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
. This family has undergone significant diversification in
primate Primates is an order (biology), order of mammals, which is further divided into the Strepsirrhini, strepsirrhines, which include lemurs, galagos, and Lorisidae, lorisids; and the Haplorhini, haplorhines, which include Tarsiiformes, tarsiers a ...
lineages. * The
leukocyte immunoglobulin-like receptors The leukocyte immunoglobulin-like receptors (LILR) are a family of receptors possessing extracellular immunoglobulin domains. They are also known as CD85, ILTs and LIR, and can exert immunomodulatory effects on a wide range of immune cells.Damia ...
(LILR) family contains 13 genes, including two
pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...
s. They have 2-4 Ig domains. One member,
LILRA3 Leukocyte immunoglobulin-like receptor subfamily A member 3 (LILR-A3) also known as CD85 antigen-like family member E (CD85e), immunoglobulin-like transcript 6 (ILT-6), and leukocyte immunoglobulin-like receptor 4 (LIR-4) is a protein that in hum ...
, 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. * The paired type 2 immunoglobulin like receptor (PILR) family contains two genes, PILRA (inhibiting) and PILRB (activating). They have a single extracellular Ig domain with a siglec-like structure. * The signal regulatory protein (SIRP) family contains three genes,
SIRPA Sirpa is a village development committee in Rolpa District in the Rapti Zone of north-eastern Nepal. At the time of the 1991 Nepal census The 1991 Nepal census was a widespread national census conducted by the Nepal Central Bureau of Statisti ...
(inhibiting),
SIRPB1 Signal-regulatory protein beta-1 is a protein that in humans is encoded by the ''SIRPB1'' gene. SIRPB1 has also recently been designated CD172B (cluster of differentiation 172B). The protein encoded by this gene is a member of the signal-regulat ...
(activating), and SIRPG (non-signaling), with the more distantly related SIRPD and SIRPB2 not yet well characterized. SIRPA interacts with
CD47 CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and al ...
, a regulator of
phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...
. This family also interacts with
surfactant protein D Surfactant protein D, also known as SP-D, is a lung surfactant protein part of the collagenous family of lectins called collectin. In humans, SP-D is encoded by the ''SFTPD'' gene and is part of the innate immune system. Each SP-D subunit is com ...
. * The carcinoembryonic antigen-related cell adhesion (CEACAM) family contains 12 genes with one or more Ig domains. They are expressed broadly, especially in
endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...
and
epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
and have roles in cell-cell recognition. They have been extensively studied for their role in cancer and have been used as cancer
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s. * The siglec family contains 15 genes divided into two evolutionarily related groups. This family has three members with activating motifs, Siglec-14, Siglec-15, and Siglec-16. These proteins bind
sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" () was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is ''N''-acetylneuraminic acid ...
s, and are often targeted by pathogens. *
TIGIT TIGIT ( ; also called T cell immunoreceptor with Ig and ITIM domains) is an immune receptor present on some T cells and natural killer cells (NK). It is also identified as WUCAM and Vstm3. TIGIT could bind to CD155 (PVR) on dendritic cells (DCs), ...
(T cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor that forms a nonhomologous but functional pair with DNAM1 (CD226).


C-type lectin-like receptors

C-type lectin-like receptors (CLRs) contain one or more
C-type lectin A C-type lectin (CLEC) is a type of carbohydrate-binding protein known as a lectin. The C-type designation is from their requirement for calcium for binding. Proteins that contain C-type lectin domains have a diverse range of functions including c ...
(Ca2+ dependent carbohydrate-binding lectin) domains. Example pairs include: *
CD94 CD94 (Cluster of Differentiation 94), also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human gene. The protein encoded by CD94 gene is a lectin, cluster of differentiation and a receptor that is involved in cell ...
/
NKG2 NKG2 also known as CD159 (Cluster of Differentiation 159) is a receptor for natural killer cells (NK cells). There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to m ...
, expressed in NK and some T cells and interacts with the ligand
HLA-E HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the ''HLA-E'' gene. The human HLA-E is a non-classical MHC class I molecule that is characterized by a lim ...
. * Dendritic cell immunoreceptor (DCIR)/ dendritic cell immunoactivating receptor (DCAR), characterized as a pair in mice, though no human DCAR has been identified. * 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 A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
has been extensively studied for its role in NK activation using
laboratory mice The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory animal sources for these mice are usually of the species ''Mus musculus''. They a ...
as a
model organism A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mo ...
, but has no homologous gene cluster in the human genome. The KIR family is the functional equivalent.


References

{{reflist, 30em Immune receptors Signal transduction