Co-receptor
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.
Properties
The term co-receptor is prominent in literature regarding signal transduction, the process by which external stimuli regulate internal cellular functioning.[1] 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.[2] 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.[1]
Co-receptors are proteins that maintain a three-dimensional structure. The large extracellular domains make up approximately 76–100% of the receptor.[2] The motifs that make up the large extracellular domains participate in ligand binding and complex formation.[3] The motifs can include glycosaminoglycans, EGF repeats, cysteine residues or ZP-1 domains.[2] 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.[2] 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.[2]
Localization and function
Depending on the type of ligand a co-receptor binds, its location and function can vary. Various ligands include
Some classical examples
CD family
The CD family of co-receptors are a well-studied group of extracellular receptors found in immunological cells.
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 is infamously the primary receptor that HIV envelope glycoprotein GP120 binds to.[6] In comparison, CD28 acts as a ‘co-coreceptor’ (costimulatory receptor) 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.[6]
CCR family of receptors
The CCR family of receptors are a group of
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.[7][8] 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.[7]
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
Inherited co-receptor autosomal disorders
Many co-receptor-related disorders occur due to mutations in the receptor's coding gene. LRP5 (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.[9]
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.[2] Mutations in LRP1 have also been found in cases of Familial Alzheimer's disease [2]
Loss of function mutations in the Cryptic co-receptor can lead to random organ positioning due to developmental left-right orientation defects.[2]
Gigantism is believed to be caused, in some cases, by a loss of function of the Glypican 3 co-receptor.[2]
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 angiogenesis by binding vascular endothelial growth factor (VEGF).[10]
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.
HIV
In order to infect a cell, the envelope glycoprotein GP120 of the HIV 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.[12] 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.[12] 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.[13] Recent evidence suggests that some forms of HIV also use the large integrin a4b7 receptor to facilitate increased binding efficiency in mucosal tissues.[13]
Hepatitis C
The
Blockade as a treatment for autoimmunity
It is possible to perform a CD4 co-receptor blockade, using
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
Most HIV-based co-receptor research focuses on the CCR5 co-receptor. The majority of HIV strains use the CCR5 receptor.[16] HIV-2 strains can also use the CXCR4 receptor[17] 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)
Cancer
Cancer-based research into co-receptors includes the investigation of
See also
References
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- ^ a b c Guo D, Jia Q. et al (1995). "Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains and association with endothelial cell proliferation". J Biol Chem 270 (12): 6729–6733.
- ^ Bobbitt, K.R., Justement, L.B. 2000. Regulation of MHC class II signal transduction by the B cell coreceptors CD19 and CD22.
- ^ a b Wang, J., Meihers, R., Xiong, Y., Lui, J., Sakihama, T., Zhang, R., Joachimiak, A., Reinherz, E.L. 2001. Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule. Proc. Natl Acad Sci USA: Vol. 98, No. 19, pp. 10799-10804.
- ^ a b c Boehme, S.A., Zheng, L., Lenardo, M.J. 1995. Analysis of the CD4 coreceptor and activation-induced costimulatory molecules in antigen-mediated mature T lymphocyte death. The Journal of Immunology. 155:1703-1712.
- ^ a b c d e f Berson, J.F., Doms, R.W. 1998. Structure-function studies of the HIV-1 coreceptors. Seminars in Immunology, Vol. 10 pp. 237–248.
- ^ a b Bleul, C.C., Wu, L., Hoxie, J.A., Springer, T.A., Mackay, C.R. 1996. The HIV receptors CXCR4 and CCR5 are differentially expressed and regulated on human T-cells. Proc. Natl. Acad. Sci. USA. Vol. 94, pp 1925–1930.
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- ^ a b Matyas, G. R., Wieczorek, L., Bansal, D., Chenine, A., Sanders-Buell, E., Tovanabutra, S., Kim, J. H., Polonis, V., Alving, C. R.(2010). Inhibition of HIV-1 infection of peripheral blood mononuclear cells by a monoclonal antibody that binds to phosphoinositides and induces secretion of beta-chemokines. Biochemical and Biophysical Research Communications, 402, 808-812.
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