The glycoprotein (GP) IIb-IIIa complex isthe receptor for fibrinogen,fibronectin and von Willebrand factor on the surface of activated platelets that mediates platelet aggregation.The GP IIb-IIIa complex contains two subunits; an a subunit, GP IIb, and a smaller 8 subunit, GP IIIa. To identify the subunits of GP IIb-IIIa responsible for fibrinogen binding, we examined the ability of purified subunitsto bind to immobilized fibrinogen. Both the GP IIb and the GP III a subunits have fibrinogen binding activity, suggesting that fibrinogen binds to multiple sites onthe GP I Ib-IIIa complex.A GP Ilb-IIIa-like complex has been identified on endothelial cells which is immunoreactive with antibodies raised against platelet GP IIb-III a. This complex binds a similar broadspectrum of adhesive proteins as plateletGP IIb-IIIa and appears to mediate the attachment of endothelial cells to the extracellular matrix. We have established, however, that while GP Ilia in endothelial cells is the same primary translation product as platelet GP Ilia, the endothelialcell "GP lib" is a different, but closely related, protein from platelet GP lib. This close relationship of the receptors on these two cells is reflective of recent observations in several laboratories which have shown that a wide variety of cells contain surface glycoproteins which have structural and functionalsimilarities to the GP IIb-IIIa complexinplatelets and the "GP IIb-IIIa-like" complex in endothelial cells.These glycoproteins, which have been termed "integrins" or "cytoadhesins", are complexes of highly homologous a and 8 subunits, mediate cell-cell or cel 1-substrata interactions, and may also bind the RGD sequence on adhesive proteins. Although in vertebrates this family includes at least ten receptor complexes, there are only three known 8 subunits, each of which defines a subset of receptors. One is GP IIIa, the 8 subunit for GP IIb-IIIa and the vitronectin receptor; another is the 8 subunit for the fibronectin receptors and the very late antigens on lymphocytes; the third is the 8subunit of the Mac-1, LFA-1, and P150/95 antigens on leukocytes. These three 6 subunits have been cloned and sequenced. Each contains 746-777 amino acids, a singletransmembrane domain near the carboxy terminus, 56 cysteines in identical positionsof the proteins, 31 of which are clustered into four repeats, and an overall identity in 45-47% of their amino acids. The asubunits are more diverse in size but appear to have a similar degree of homology.The available sequence information indicates that they contain a single transmembrane domain near their carbody terminii and four tandem repeats near their amino terminii which include sequences indicativeof four Ca2+-binding sites. These may account for the known Ca2+-binding properties of GP IIb. GP I Ib-IIIa and the other adhesive protein receptors therefore appear to have two membrane insertion sites, one on each subunit,with short cytoplasmic domains derived from the carboxy terminii of the two subunits. The amino terminii along with most ofthe mass of these proteins is extracellular. It can be anticipated that the highlyhomologous sequences between GP IIb-IIIa and the other adhesive protein receptors will help identify the functional domainswhich have been conserved since their evolutionary divergences.
Cysteine Substitution of Transmembrane Domain Amino Acids Alters the Ethanol Inhibition of GluN1/GluN2A N-Methyl-d-Aspartate Receptors
