The selectins (cluster of differentiation 62 or CD62) are a family of cell adhesion molecules (or CAMs). All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.
Structure All three known members of the selectin family (L-, E-, and P-selectin) share a similar cassette structure: an N-terminal, calcium-dependent lectin domain, an epidermal growth factor (EGF)-like domain, a variable number of consensus repeat units (2, 6, and 9 for L-, E-, and P-selectin, respectively), a transmembrane domain (TM) and an intracellular cytoplasmic tail (cyto). The transmembrane and cytoplasmic parts are not conserved across the selectins being responsible for their targeting to different compartments. Though they share common elements, their tissue distribution and binding kinetics are quite different, reflecting their divergent roles in various pathophysiological processes.
Types There are three subsets of selectins:
E-selectin (in endothelial cells) L-selectin (in leukocytes) P-selectin (in platelets and endothelial cells) L-selectin is the smallest of the vascular selectins, expressed on all granulocytes and monocytes and on most lymphocytes, can be found in most leukocytes. P-selectin, the largest selectin, is stored in α-granules of platelets and in Weibel–Palade bodies of endothelial cells, and is translocated to the cell surface of activated endothelial cells and platelets. E-selectin is not expressed under baseline conditions, except in skin microvessels, but is rapidly induced by inflammatory cytokines. These three types share a significant degree of sequence homology among themselves (except in the transmembrane and cytoplasmic domains) and between species. Analysis of this homology has revealed that the lectin domain, which binds sugars, is most conserved, suggesting that the three selectins bind similar sugar structures. The cytoplasmic and transmembrane domains are highly conserved between species, but not conserved across the selectins. These parts of the selectin molecules are responsible for their targeting to different compartments: P-selectin to secretory granules, E-selectin to the plasma membrane, and L-selectin to the tips of microfolds on leukocytes.
Etymology The name selectin comes from the words "selected" and "lectins," which are a type of carbohydrate-recognizing protein.
Function Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes, including post-ischemic inflammation in muscle, kidney and heart, skin inflammation, atherosclerosis, glomerulonephritis and lupus erythematosus and cancer metastasis. During an inflammatory response, P-selectin is expressed on endothelial cells first, followed by E-selectin later. Stimuli such as histamine and thrombin cause endothelial cells to mobilize immediate release of preformed P-selectin from Weible-Palade bodies inside the cell. Cytokines such as TNF-alpha stimulate transcription and translation of E-selectin and additional P-selectin, which account for the delay of several hours. As the leukocyte rolls along the blood vessel wall, the distal lectin-like domain of the selectin binds to certain carbohydrate groups presented on proteins (such as PSGL-1) on the leukocyte, which slows the cell and allows it to leave the blood vessel and enter the site of infection. The low-affinity nature of selectins is what allows the characteristic "rolling" action attributed to leukocytes during the leukocyte adhesion cascade. Each selectin has a carbohydrate recognition domain that mediates binding to specific glycans on apposing cells. They have remarkably similar protein folds and carbohydrate binding residues, leading to overlap in the glycans to which they bind. Selectins bind to the sialyl Lewis X (SLex) determinant "NeuAcα2-3Galβ1-4(Fucα1-3)GlcNAc." However, SLex, per se, does not constitute an effective selectin receptor. Instead, SLex and related sialylated, fucosylated glycans are components of more extensive binding determinants. The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1 (PSGL-1), which is a mucin-type glycoprotein expressed on all white blood cells. Neutrophils and eosinophils bind to E-selectin. One of the reported ligands for E-selectin is the sialylated Lewis X antigen (SLex). Eosinophils, like neutrophils, use sialylated, protease-resistant structures to bind to E-selectin, although the eosinophil expresses much lower levels of these structures on its surface. Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-galactosidase-resistant structures, clearly different from those reported for E-selectin, and suggest disparate roles for P-selectin and E-selectin during recruitment during inflammatory responses.
Bonding mechanisms Selectins have hinge domains, allowing them to undergo rapid conformational changes in the nanosecond range between 'open' and 'closed' conformations. Shear stress on the selectin molecule causes it to favor the 'open' conformation. In leukocyte rolling, the 'open' conformation of the selectin allows it to bind to inward sialyl Lewis molecules farther up along the PSGL-1 chain, increasing overall binding affinity—if the selectin-sialyl Lewis bond breaks, it can slide and form new bonds with the other sialyl Lewis molecules down the chain. In the 'closed' conformation, however, the selectin is only able to bind to one sialyl Lewis molecule, and thus has greatly reduced binding affinity. The result of such is that selectins exhibit catch and slip bond behavior—under low shear stresses, their bonding affinities are actually increased by an increase in tensile force applied to the bond because of more selectins preferring the 'open' conformation. At high stresses, the binding affinities are still reduced because the selectin-ligand bond is still a normal slip bond. It is thought that this shear stress threshold helps select for the right diameter of blood vessels to initiate leukocyte extravasation, and may also help prevent inappropriate leukocyte aggregation during vascular stasis.
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