Name the 4 Main Families of Cell Adhesion Molecules
Adhesion molecules
These cell surface glycoproteins can be divided into 4 chief groups :
- The integrin family (eight subfamilies; for example beta 1 : CD29, VLA=Very Tardily Activator ; beta 2 : leukocyte integrins such as CD11/CD18)
- The immunoglobulin superfamily (for example LFA-two=CD2 , LFA-3=CD58 , ICAMs=intercellular adhesion molecules , VCAM-i=vascular adhesion molecule-one)
- Selectins (P, E, L) ; they incorporate lectin domain
- Cadherins (Eastward=epithelial, P=placental, N=neural subclasses)
The binding sites are different for each of these adhesion molecules. They are essential for contacts between the cells and betwixt the cells and extracellular matrix (ECM).
Integrins are cell-surface receptors that mediate adhesion to the extracellular matrix (ECM) and prison cell-cell interactions. Most cells limited several integrins that recognize a range of cell surface- and ECM- associated ligands. Individual integrins often bind more than 1 ligand. They play multiple roles in differentiation and cell advice.
Integrins are heterodimers of alpha and beta subunits :
Many integrins recognize the sequence RGD (Arg-Gly-Asp).
In mammals, at least xx integrin heterodimers, comprised of 14 different types of alpha subunits and 8 types of beta subunits are known ( v ). A unmarried beta chain can interact with multiple alpha bondage forming integrins that demark dissimilar ligands. Some of the subunits are expressed exclusively on one type of cells, for instance:
- beta 2 on leukocytes ; lymphocytes can collaborate via integrins with proteoglycans and glycosaminoglycans which are the major components of ECM. Such interactions are important for lymphocyte migration, recognition, activation and differentiation ( eight )
- integrins alpha3 beta1 and alpha6 beta4 are abundant receptors on keratinocytes for laminin-5 which is the major component of the basement membrane in the skin.
Some integrins may require activation in order to bind their ligand and anchor the jail cell to the ECM or to another cell. For case alphaIIb beta3 integrin (Ca(two+) dependent heterodimer) from platelets cannot bind fibrinogen (blood fibrous protein) unless the platelets are are activated by binding collagen or thrombin in a forming clot. This activation leads to conformational change in the integrin which is connected with cytoskeleton remodeling. Adhesion mediated by alphaIIb beta3 integrin is selective and irreversible. Information technology plays a central role in thrombus formation in health and disease (the simultaneous occupation of receptors on adjacent platelets with dimeric fibronectin molecules leads to platelet aggregation). As well fibrinogen it also binds von Willebrant Factor (vWF), fibronectin, vitronectin and thrombospondin.( iii )
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The Ig superfamily members contain I-domains. X-ray crystallography revealed that I-domain consists of central cadre of v parallel and one short antiparallel beta-strands surrounded at the outer surface by 7 alpha-helices and loop regions. It contains about 200 amino acrid residues. Each I-domain has the disulphide bridge. ( half dozen )
Ane of the member of the Ig superfamily is CD2, a glycoprotein receptor of T-cells. It mediates cell-cell adhesion past binding to the surface molecule LFA-3 (from the same group) present on many cells including APC (antigen presenting cells). CD2 has 2 extracellular I-domains. N-concluding domain which is responsible for adhesion contains a single high-mannose type oligosaccharide. The absence of this N-glycan leads to loss of both structural and functional properties of CD2 ( half-dozen )
CD2 - LFA 3 adhesion plays an of import role in faciliating TCR/CD3 recognition of antigens presented by the MHC class 2. CD2 is also required for T-cell activation.
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Selectins are membrane-attached mosaic proteins recognizing carbohydrates.
Due to the selectins white blood cells can migrate from blood vessels to the tissues. They adhere selectively to the walls of claret vessels called high endothelial venules (microscopic vessels, less than 30 microns in diameter). This adhesion is mediated past the Fifty-selectins (homing receptors) on fiftyymphocytes. They decide the endothelial cells to which a lymphocytes will adhere (for example some of them bind just in peripheral lymph nodes the others in the intestinal Peyer'due south patches)
In contrast to the homing receptor, the two other selectins (P and E) are plant on endothelial cells and and so merely when they are actively alluring leukocytes (they are transiently expressed on endothelial cells).
When a tissue is infected, information technology secretes cytokines (IL-ane, TNF) which stimulate endothelial cells in the venules to express P and E selectins. The white blood cells adhere to these selectins because their carohydrate coats contain complementary structures. Thus leukocytes can leave the vessels and drift into the infected tissue.
P and E selectins appear on endothelial cells at different times and recruit different types of ehite claret cells.
- P-selectins are expressed earlier (a few minutes after the infection begins) considering endothelial cells have an internal stock-pile of them. They depict leukocytes that deed during the earliest phases of the immunologic defense. P-selectins binds sialylated, fucosylated carbohydrate ligands such every bit sialyl-LeX.
- East-selectins (ELAM-1) are synthesized only when they are required. Thus it takes longer to appear (most four hours later on the beginning of infection ; then the level of E-selectins gradually fades away). They are involved in recruiting leukocytes such as neutrophils and macrophages to the inflammation sites. E- selectins demark sialyl-LeX.
In some diseases white blood cells enter the tissues where they not belong and cause their harm. For example the inflammation of rheumatoid arthritis occurs when leukocytes enter the joints and release protein-chopping enzymes, oxygen radicals and other toxic factors. ( seven )
Cell-adhesion molecules may play a role in other diseases such as spread of the cancer cells throughout the body. For example the carbohydrates recognized by ELAM-one are expressed on different tumour cells.
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Lectins are saccharide binding proteins which are abundant in living organisms from leaner to mammals.
The machinery of carbohydrate binding :
Relatively low affinity binding sites for monosaccharides are formed at shallow indentations on poly peptide surface. Selectivity is accomplished through a combination of hydrogen bonding to the saccharide hydroxyl groups with van der Waals packing, oft confronting aromatic amino acid side bondage. Coordination with metal ions may occasionally play a part too.
College selectivity is accomplished by extending binding sites through boosted direct and water-mediated contacts between oligosaccharides and protein surface. Dramatically increased affinity for oligosaccharides results from clustering of simple binding sites in oligomers of the lectin polypeptides. The geometry of such oligomers enables the lectins to distinguish surface arrays of polysaccharides and to cantankerous-link glycoconjugates. ( ten )
LECTINS ARE STRUCTURALLY AND FUNCTIONALLY Various
- C-type CRDs are Ca(ii+)-dependent. They are involved in :
- sorting of glycoproteins ; for example asialoglycoprotein receptor which contains C-final C-CRD mediates clearance of dissimilar glycoproteins from the circulation which is triggered past removal of North-terminal sialic acrid residues from complex N-linked oligosaccharides
- recognizing of dissimilar carbohydrates ; they are N-last parts of selectins
- I-type lectins (sialoadhesins) contain two or more I-domains ; they recognize terminal sialic acid residues. The affinity of receptor- ligand interaction is determined by the number of sialic acid residues associated with the ligand glycoprotein and by advisable sialic acrid presentation past the underlying polypeptide backbone.
- For case CD22- an Ig-superfamily B lymphocyte specific adhesion receptor recognizes sialic acid linked (alpha 2,vi) to the terminal N-linked oligosaccharides on selected prison cell surface glycoproteins. It requires an intact ligand-associated sialic acid polyhydroxyl side chain ; modifications abrogate the interactions.
- The other members of I- blazon lectins : CD33 and Mag ( myelin associated glycoprotein) recognize sialic acid in (alpha 2,three) linkage ( four )
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Cadherins are integral transmembrane glycoproteins which mediate Ca(2+) -dependent prison cell-cell adhesion amidst the almost tissues. It is crucial for the mutual association of vertebrate cells.
For example in epithelial cells E-cadherins stabilize the junction interacting homophically with E-cadherin molecules from adjacent cells. E-cadherin adhesion organisation is dumb in cancer cells.Thus cancer cells can spread throughout the torso.
Cadherins are associated with the actin cytoskeleton through the cytoplasmic proteins, catenins (alpha, beta and gamma=plakoglobin); beta- catenin or plakoglobin is associated directly with the cadherin and alpha- catenin is bound to beta or gamma catenin and to the actin cytoskeleton.
The anchorage of cadherins to the cytoskeleton appears to exist regulated by tyrosine phosphorylation.
- North- cadherins (NCAMs) are sialylated to dissimilar extent during the organism evolution. In embryonic neural tissue polysialic acid constitutes about 25 per cent (information technology leads to the lower adhesive backdrop what is necessary because of the forming of neural tissue. NCAMs from adult tissues contain but one third as much sialic acid and have higher adhesive properties (contacts between cells are established). Thus the strenght of the cell- cell adhesion is modified during differentiation by differential glycosylation of NCAMs.
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Recognition and adhesion
Other functions of glycoproteins
Contents
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Source: http://www.cryst.bbk.ac.uk/pps97/assignments/projects/emilia/Adh_mol.HTM
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