Co-receptor
Encyclopedia
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand
recognition and initiate biological processes, such as entry of a pathogen into a host cell.
, the process by which external stimuli regulate internal cellular functioning. The key to optimal cellular functioning is maintained by possessing specific machinery that can carry out tasks efficiently and effectively. Specifically, the process through which intermolecular reactions forward and amplify extracellular signals across the cell surface has developed to occur by two mechanisms.
First, cell surface receptors can directly transduce signals by possessing both serine
and threonine
or simply serine in the cytoplasmic domain. They can also transmit signals through adaptor molecules through their cytoplasmic domain which bind to signalling motifs. Secondly, certain surface receptors lacking a cytoplasmic domain can transduce signals through ligand binding. Once the surface receptor binds the ligand it forms a complex with a corresponding surface receptor to regulate signalling. These categories of cell surface receptors are prominently referred to as co-receptors. Co-receptors are also referred to as accessory receptors, especially in the fields of biomedical research and immunology.
Co-receptors are proteins that maintain a three dimensional structure. The large extracellular domains make up approximately 76-100% of the receptor. The motifs that make up the large extracellular domains participate in ligand binding and complex formation.
The motifs can include glycosaminoglycans, EGF repeats, cysteine residues or ZP-1 domains. The variety of motifs leads to co-receptors being able to interact with two to nine different ligands, which themselves can also interact with a number of different co-receptors.
Most co-receptors lack a cytoplasmic domain and tend to be GPI-anchored, though a few receptors have been identified which contain short cytoplasmic domains that lack intrinsic kinase
activity.
, fibroblast growth factors, transforming growth factors, vascular endothelial growth factors and epidermal growth factor
s. Co-receptors prominent in embryonic tissue have an essential role in morphogen
gradient formation or tissue differentiation. Co-receptors localized in endothelial cells function to enhance cell proliferation and cell migration
.
With such variety in regards to location, co-receptors can participate in many different cellular activities. Co-receptors have been identified as participants in cell signalling cascades, embryonic development, cell adhesion regulation, gradient formation, tissue proliferation and migration.
acting as a co-receptor to the T cell receptor
(TCR) to bind major histocompatibility complex II (MHC-II). This binding is particularly well-studied in T-cells where it serves to activate T-cells that are in their resting (or dormant) phase and to cause active cycling T-cells to undergo programmed cell death
. Boehme et al. demonstrated this interesting dual outcome by blocking the binding of CD4 to MHC-II which prevented the programmed cell death reaction that active T-cells typically display.
The CD4 receptor is composed of four concatamerized Ig-like domains and is anchored to the cell membrane by a single transmembrane domain. CD family receptors are typically monomer
s or dimers
, though they are all primarily extracellular proteins. The CD4 receptor in particular interacts with murine MHC-II following the “ball-on-stick” model, where the Phe-43 ball fits into the conserved hydrophobic α2 and β2 domain residues. During binding with MHC-II, CD4 maintains independent structure and does not form any bonds with the TCR receptor.
The members of the CD family of co-receptors have a wide range of function. As well as being involved in forming a complex with MHC-II with TCR to control T-cell fate, the CD4 receptor also is infamously the primary receptor that HIV envelope glycoprotein GP120 binds to. In comparison, CD28
acts as a ‘co-coreceptor’ for the MHC-II binding with TCR and CD4. CD28 increases the Il-2 secretion from the T-cells if it is involved in the initial activation; however, CD28 blockage has no effect on programmed cell death after the T-cell has been activated.
(and its near-homologue CXCR4
) which acts as the primary co-receptor for HIV viral infection. The HIV envelope glycoprotein GP120 binds to CD4 as its primary receptor, CCR5 then forms a complex with CD4 and HIV, allowing viral entry into the cell. CCR5 is not the only member of the CCR family that allows for HIV infection. Due to the commonality of structures found throughout the family, CCR2
b, CCR3
, and CCR8 can be utilized by some HIV strains as co-receptors to facilitate infection. CXCR4 is very similar to CCR5 in structure. While only some HIV strains can utilize CCR2b, CCR3 and CCR8, all HIV strains can infect through CCR5 and CXCR4.
CCR5 is known to have an affinity for macrophage inflammatory protein
(MIP) and is thought to play a role in inflammatory immunological responses. The primary role of this receptor is less understood than its role in HIV infection, as inflammation responses remain a poorly understood facet of the immune system. CCR5’s affinity for MIP makes it of great interest for practical applications such as tissue engineering
, where attempts are being made to control host inflammatory and immunological responses at a cellular signalling level. The affinity for MIP has been utilized in-vitro to prevent HIV infection through ligand competition; however, these entry-inhibitors have failed in-vivo due to the highly adaptive nature of HIV and toxicity concerns.
(low-density lipoprotein receptor-related protein 5) acts as a co-receptor for the Wnt-family of glycoproteins which regulate bone mass. Malfunctions in this co-receptor lead to lower bone density and strength which contribute to osteoporosis
.
Loss of function mutations in LRP5 have been implicated in Osteoporosis-pseudoglioma syndrome, Familial exudative vitreoretinopathy, and a specific missense mutation
in the first β-propeller region of LRP5 can lead to abnormally high bone density or osteopetrosis
. Mutations in LRP1 have also been found in cases of Familial Alzheimer's disease
Loss of function mutations in the Cryptic co-receptor can lead to random organ positioning due to developmental left-right orientation defects.
Gigantism
is believed to be caused, in some cases, by a loss of function of the Glypican 3
co-receptor.
by binding vascular endothelial growth factor
(VEGF).
Angiogenesis is important in embryonic development but it is also a fundamental process of tumor growth. Deletion of the gene in Caecam1-/- mice results in a reduction of the abnormal vascularization seen in cancer and lowered nitric oxide production, suggesting a therapeutic possibility through targeting of this gene. The neuropilin
co-receptor family mediates binding of VEGF in conjunction with the VEGFR1/VEGFR2 and Plexin
signaling receptors, and therefore also plays a role in tumor vascular development.
CD109
acts as a negative regulator of the tumor growth factor β (TGF-β) receptor. Upon binding TGF-β, the receptor is internalized via endocytosis
through CD109's action which lowers signal transmission into the cell. In this case, the co-receptor is functioning in a critical regulatory manner to reduce signals that instruct the cell to grow and migrate – the hallmarks of cancer. In conjunction, the LRP co-receptor family also mediates binding of TGF-β with a variety of membrane receptors.
Interleukins 1, 2, and 5 all rely on interleukin co-receptors to bind to the primary interleukin receptors.
Syndecans 1 and 4 have been implicated in a variety of cancer types including cervical, breast, lung, and colon cancer, and abnormal expression levels have been associated with poorer prognosis.
virus interacts with CD4
(acting as the primary receptor) and a co-receptor: either CCR5
or CXCR4
. This binding results in membrane fusion and the subsequent intracellular signaling that facilitates viral invasion. In approximately half of all HIV cases, the viruses using the CCR5 co-receptor seem to favor immediate infection and transmission while those using the CXCR4 receptor do not present until later in the immunologically suppressed stage of the disease. The virus will often switch from using CCR5 to CXCR4 during the course of the infection, which serves as an indicator for the progression of the disease. Recent evidence suggests that some forms of HIV also use the large integrin a4b7 receptor to facilitate increased binding efficiency in mucosal tissues.
virus requires the CD81
co-receptor for infection. Studies suggest that the tight junction protein Claudin-1 (CLDN1) may also play a part in HCV entry. Claudin family abnormalities are also common in hepatocellular carcinoma, which can result from HPV infection.
Both the CCR5 and the CXCR4 co-receptors are seven-trans-membrane (7TM) G protein-coupled receptors.
Different strains of HIV work on different co-receptors, although the virus can switch to utilizing other co-receptors. For example, R5X4 receptors can become the dominant HIV co-receptor target in main strains. HIV-1 and HIV-2 can both use the CCR8 co-receptor. The crossover of co-receptor targets for different strains and the ability for the strains to switch from their dominant co-receptor can impede clinical treatment of HIV. Treatments such as WR321 mAb
can inhibit some strains of CCR5 HIV-1, preventing cell infection. The mAb causes the release of HIV-1-inhibitory b-chemokines, preventing other cells from becoming infected.
activated co-receptors, such as Transforming Growth Factor (TGF-β) co-receptors. Expression of the co-receptor endoglin
, which is expressed on the surface of tumor cells, is correlated with cell plasticity and the development of tumors.
Another co-receptor of TGF-β is CD8. Although the exact mechanism is still unknown, CD8 co-receptors have been shown to enhance T-cell activation and TGF-β-mediated immune suppression.
TGF-β has been shown to influence the plasticity of cells through integrin
and focal adhesion kinase. The co-receptors of tumor cells and their interaction with T-cells provide important considerations for tumor immunotherapy
.
Recent research into co-receptors for p75, such as the sortilin co-receptor, has implicated sortillin in connection to neurotrophins, a type of nerve growth factor.
The p75 receptor and co-receptors have been found to influence the aggressiveness of tumors, specifically via the ability of neurotrophins to rescue cells form certain forms of cell death.
Sortilin, the p75 co-receptor, has been found in natural killer cells, but with only low levels of neurotrophin receptor. The sortilin co-receptor is believed to work with a neurotrophin homologue that can also cause neurotrophin to alter the immune response.
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
recognition and initiate biological processes, such as entry of a pathogen into a host cell.
Co-receptor Properties
The term co-receptor is prominent in literature regarding signal transductionSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
, the process by which external stimuli regulate internal cellular functioning. The key to optimal cellular functioning is maintained by possessing specific machinery that can carry out tasks efficiently and effectively. Specifically, the process through which intermolecular reactions forward and amplify extracellular signals across the cell surface has developed to occur by two mechanisms.
First, cell surface receptors can directly transduce signals by possessing both serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
and threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
or simply serine in the cytoplasmic domain. They can also transmit signals through adaptor molecules through their cytoplasmic domain which bind to signalling motifs. Secondly, certain surface receptors lacking a cytoplasmic domain can transduce signals through ligand binding. Once the surface receptor binds the ligand it forms a complex with a corresponding surface receptor to regulate signalling. These categories of cell surface receptors are prominently referred to as co-receptors. Co-receptors are also referred to as accessory receptors, especially in the fields of biomedical research and immunology.
Co-receptors are proteins that maintain a three dimensional structure. The large extracellular domains make up approximately 76-100% of the receptor. The motifs that make up the large extracellular domains participate in ligand binding and complex formation.
The motifs can include glycosaminoglycans, EGF repeats, cysteine residues or ZP-1 domains. The variety of motifs leads to co-receptors being able to interact with two to nine different ligands, which themselves can also interact with a number of different co-receptors.
Most co-receptors lack a cytoplasmic domain and tend to be GPI-anchored, though a few receptors have been identified which contain short cytoplasmic domains that lack intrinsic kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
activity.
Co-receptor Localization and Function
Depending on the type of ligand a co-receptor binds, its location and function can vary. Various ligands include interleukins, neurotrophic factorsNeurotrophic factors
Neurotrophic factors are a family of proteins that are responsible for the growth and survival of developing neurons and the maintenance of mature neurons...
, fibroblast growth factors, transforming growth factors, vascular endothelial growth factors and epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
s. Co-receptors prominent in embryonic tissue have an essential role in morphogen
Morphogen
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue...
gradient formation or tissue differentiation. Co-receptors localized in endothelial cells function to enhance cell proliferation and cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
.
With such variety in regards to location, co-receptors can participate in many different cellular activities. Co-receptors have been identified as participants in cell signalling cascades, embryonic development, cell adhesion regulation, gradient formation, tissue proliferation and migration.
CD Co-receptors
The CD family of co-receptors are a well-studied group of extracellular receptors found in immunological cells. The CD receptor family typically act as co-receptors, illustrated by the classic example of CD4CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
acting as a co-receptor to the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
(TCR) to bind major histocompatibility complex II (MHC-II). This binding is particularly well-studied in T-cells where it serves to activate T-cells that are in their resting (or dormant) phase and to cause active cycling T-cells to undergo programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
. Boehme et al. demonstrated this interesting dual outcome by blocking the binding of CD4 to MHC-II which prevented the programmed cell death reaction that active T-cells typically display.
The CD4 receptor is composed of four concatamerized Ig-like domains and is anchored to the cell membrane by a single transmembrane domain. CD family receptors are typically monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
s or dimers
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, though they are all primarily extracellular proteins. The CD4 receptor in particular interacts with murine MHC-II following the “ball-on-stick” model, where the Phe-43 ball fits into the conserved hydrophobic α2 and β2 domain residues. During binding with MHC-II, CD4 maintains independent structure and does not form any bonds with the TCR receptor.
The members of the CD family of co-receptors have a wide range of function. As well as being involved in forming a complex with MHC-II with TCR to control T-cell fate, the CD4 receptor also is infamously the primary receptor that HIV envelope glycoprotein GP120 binds to. In comparison, CD28
CD28
CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
acts as a ‘co-coreceptor’ for the MHC-II binding with TCR and CD4. CD28 increases the Il-2 secretion from the T-cells if it is involved in the initial activation; however, CD28 blockage has no effect on programmed cell death after the T-cell has been activated.
The CCR Family of Receptors
The CCR family of receptors are a group of g-protein coupled receptors (GPCRs) that normally operate as chemokine receptors. They are primarily found on immunological cells, especially T-cells. CCR receptors are also expressed on neuronal cells, such as dendrites and microglia. Perhaps the most famous and well-studied of the CCR family is CCR5CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
(and its near-homologue CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
) which acts as the primary co-receptor for HIV viral infection. The HIV envelope glycoprotein GP120 binds to CD4 as its primary receptor, CCR5 then forms a complex with CD4 and HIV, allowing viral entry into the cell. CCR5 is not the only member of the CCR family that allows for HIV infection. Due to the commonality of structures found throughout the family, CCR2
CCR2
CCR2, short for chemokine receptor 2, is a chemokine receptor.CCR2 has also recently been designated CD192 .-External links:* at...
b, CCR3
CCR3
CCR3 may refer to:* CCR3 * ICAO airport code of Florenceville Airport...
, and CCR8 can be utilized by some HIV strains as co-receptors to facilitate infection. CXCR4 is very similar to CCR5 in structure. While only some HIV strains can utilize CCR2b, CCR3 and CCR8, all HIV strains can infect through CCR5 and CXCR4.
CCR5 is known to have an affinity for macrophage inflammatory protein
Macrophage Inflammatory Protein
Macrophage Inflammatory Proteins belong to the family of chemotactic cytokines known as chemokines. Macrophage inflammatory protein-1 , MIP-1 and MIP-1 are chemokines crucial for immune responses towards infection and inflammation. In humans, there are two major forms, MIP-1α and MIP-1β that are...
(MIP) and is thought to play a role in inflammatory immunological responses. The primary role of this receptor is less understood than its role in HIV infection, as inflammation responses remain a poorly understood facet of the immune system. CCR5’s affinity for MIP makes it of great interest for practical applications such as tissue engineering
Tissue engineering
Tissue engineering is the use of a combination of cells, engineering and materials methods, and suitable biochemical and physio-chemical factors to improve or replace biological functions...
, where attempts are being made to control host inflammatory and immunological responses at a cellular signalling level. The affinity for MIP has been utilized in-vitro to prevent HIV infection through ligand competition; however, these entry-inhibitors have failed in-vivo due to the highly adaptive nature of HIV and toxicity concerns.
Clinical Significance
Because of their importance in cell signaling and regulation, co-receptors have been implicated in a number of diseases and disorders. Co-receptor knockout mice are often unable to develop and such knockouts generally result in embryonic or perinatal lethality. It is important to note that in immunology in particular, the term “co-receptor” often describes a secondary receptor used by a pathogen to gain access to the cell, or a receptor that works alongside T cell receptors such as CD4, CD8, or CD28 to bind antigens or regulate T cell activity in some way.Inherited co-receptor autosomal disorders
Many co-receptor-related disorders occur due to mutations in the receptor's coding gene. LRP5LRP5
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene.- Function :LRP5 is a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis...
(low-density lipoprotein receptor-related protein 5) acts as a co-receptor for the Wnt-family of glycoproteins which regulate bone mass. Malfunctions in this co-receptor lead to lower bone density and strength which contribute to osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
.
Loss of function mutations in LRP5 have been implicated in Osteoporosis-pseudoglioma syndrome, Familial exudative vitreoretinopathy, and a specific missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
in the first β-propeller region of LRP5 can lead to abnormally high bone density or osteopetrosis
Osteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle,...
. Mutations in LRP1 have also been found in cases of Familial Alzheimer's disease
Loss of function mutations in the Cryptic co-receptor can lead to random organ positioning due to developmental left-right orientation defects.
Gigantism
Gigantism
Gigantism, also known as giantism , is a condition characterized by excessive growth and height significantly above average...
is believed to be caused, in some cases, by a loss of function of the Glypican 3
Glypican 3
Glypican-3 is a protein that in humans is encoded by the GPC3 gene. The protein encoded by this gene is a member of the glypican family.-Structure and function:...
co-receptor.
Cancer
Carcinoembryonic antigen cell adhesion molecule-1 (Caecam1) is an immunoglobulin-like co-receptor that aids in cell adhesion in epithelial, endothelial and hematopoietic cells, and plays a vital role during vascularization and angiogenesisAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
by binding vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF).
Angiogenesis is important in embryonic development but it is also a fundamental process of tumor growth. Deletion of the gene in Caecam1-/- mice results in a reduction of the abnormal vascularization seen in cancer and lowered nitric oxide production, suggesting a therapeutic possibility through targeting of this gene. The neuropilin
Neuropilin
Neuropilin is a protein receptor active in neurons.There are two forms of Neuropilins, NRP-1 and NRP-2. They are transmembrane glycoproteins, and predominantly co-receptors for another class of proteins known as semaphorins...
co-receptor family mediates binding of VEGF in conjunction with the VEGFR1/VEGFR2 and Plexin
Plexin
A plexin is a protein which acts as a receptor for semaphorin.Genes include:* PLXNA1, PLXNA2, PLXNA3, PLXNA4A, * PLXNB1, PLXNB2, PLXNB3* PLXND1...
signaling receptors, and therefore also plays a role in tumor vascular development.
CD109
CD109
CD109 is a human gene....
acts as a negative regulator of the tumor growth factor β (TGF-β) receptor. Upon binding TGF-β, the receptor is internalized via endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
through CD109's action which lowers signal transmission into the cell. In this case, the co-receptor is functioning in a critical regulatory manner to reduce signals that instruct the cell to grow and migrate – the hallmarks of cancer. In conjunction, the LRP co-receptor family also mediates binding of TGF-β with a variety of membrane receptors.
Interleukins 1, 2, and 5 all rely on interleukin co-receptors to bind to the primary interleukin receptors.
Syndecans 1 and 4 have been implicated in a variety of cancer types including cervical, breast, lung, and colon cancer, and abnormal expression levels have been associated with poorer prognosis.
HIV
In order to infect a cell, the envelope glycoprotein GP120 of the HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
virus interacts with CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
(acting as the primary receptor) and a co-receptor: either CCR5
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
or CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
. This binding results in membrane fusion and the subsequent intracellular signaling that facilitates viral invasion. In approximately half of all HIV cases, the viruses using the CCR5 co-receptor seem to favor immediate infection and transmission while those using the CXCR4 receptor do not present until later in the immunologically suppressed stage of the disease. The virus will often switch from using CCR5 to CXCR4 during the course of the infection, which serves as an indicator for the progression of the disease. Recent evidence suggests that some forms of HIV also use the large integrin a4b7 receptor to facilitate increased binding efficiency in mucosal tissues.
Hepatitis C
The Hepatitis CHepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
virus requires the CD81
CD81
CD81 molecule, also known as CD81 , is a protein which in humans is encoded by the CD81 gene...
co-receptor for infection. Studies suggest that the tight junction protein Claudin-1 (CLDN1) may also play a part in HCV entry. Claudin family abnormalities are also common in hepatocellular carcinoma, which can result from HPV infection.
Blockade as a treatment for autoimmunity
It is possible to perform a CD4 co-receptor blockade, using antibodies, in order to lower T cell activation and counteract autoimmune disorders. This blockade appears to elicit a “dominant” effect, that is to say, once blocked, the T cells do not regain their ability to become active. This effect then spreads to native T cells which then switch to a CD4+CD25+GITR+FoxP3+ T regulatory phenotype.Current Areas of Research
Currently, the two most prominent areas of co-receptor research are investigations regarding HIV and cancer. HIV research is highly focused on the adaption of HIV strains to a variety of host co-receptors. Cancer research is mostly focused on enhancing the immune response to tumor cells, while some research also involves investigating the receptors expressed by the cancerous cells themselves.HIV & co-receptors
Most HIV-based co-receptor research focuses on the CCR5 co-receptor. The majority of HIV strains use the CCR5 receptor. HIV-2 strains can also use the CXCR4 receptor though the CCR5 receptor is the more predominantly targeted of the two.Both the CCR5 and the CXCR4 co-receptors are seven-trans-membrane (7TM) G protein-coupled receptors.
Different strains of HIV work on different co-receptors, although the virus can switch to utilizing other co-receptors. For example, R5X4 receptors can become the dominant HIV co-receptor target in main strains. HIV-1 and HIV-2 can both use the CCR8 co-receptor. The crossover of co-receptor targets for different strains and the ability for the strains to switch from their dominant co-receptor can impede clinical treatment of HIV. Treatments such as WR321 mAb
Mab
Mab or MAB may refer to:* Queen Mab, a fairy in Shakespeare's Romeo and Juliet and later works of English literature.* Mab , one of the moons of Uranus, named after Queen Mab* Manufacture d'armes de Bayonne, a French firearms manufacturer...
can inhibit some strains of CCR5 HIV-1, preventing cell infection. The mAb causes the release of HIV-1-inhibitory b-chemokines, preventing other cells from becoming infected.
Cancer & co-receptors
Cancer-based research into co-receptors includes the investigation of growth factorGrowth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
activated co-receptors, such as Transforming Growth Factor (TGF-β) co-receptors. Expression of the co-receptor endoglin
Endoglin
Endoglin is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex.The protein consists of a homodimer of 180 kDA with disulfide links....
, which is expressed on the surface of tumor cells, is correlated with cell plasticity and the development of tumors.
Another co-receptor of TGF-β is CD8. Although the exact mechanism is still unknown, CD8 co-receptors have been shown to enhance T-cell activation and TGF-β-mediated immune suppression.
TGF-β has been shown to influence the plasticity of cells through integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
and focal adhesion kinase. The co-receptors of tumor cells and their interaction with T-cells provide important considerations for tumor immunotherapy
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
.
Recent research into co-receptors for p75, such as the sortilin co-receptor, has implicated sortillin in connection to neurotrophins, a type of nerve growth factor.
The p75 receptor and co-receptors have been found to influence the aggressiveness of tumors, specifically via the ability of neurotrophins to rescue cells form certain forms of cell death.
Sortilin, the p75 co-receptor, has been found in natural killer cells, but with only low levels of neurotrophin receptor. The sortilin co-receptor is believed to work with a neurotrophin homologue that can also cause neurotrophin to alter the immune response.