title: Adhesive and signaling properties of a naturally occurring allele of glycoprotein IIIa with an amino acid substitution within the ligand binding domain-the Pena/Penb platelet alloantigenic epitopes.
abstract: Platelet membrane glycoprotein IIIa (GPIIIa) is the most polymorphic integrin subunit in man, with at least seven recognized allelic isoforms present in the human gene pool. Whether these allelic variants of the GPIIb-IIIa complex differ in the ability to interact with the adhesive ligand fibrinogen (Fg) is still unknown. Since the Pena and Penb allelic forms of GPIIIa are distinguished by a single Arg143Gln amino acid substitution within the RGD binding domain of GPIIIa and anti-Pena human alloantibodies have been shown to bind GPIIb-IIIa on the platelet surface and inhibit ADP-induced platelet aggregation, we expressed both forms of this integrin in Chinese hamster ovary (CHO) cells and examined the relative adhesive properties. Both allelic forms of GPIIb-IIIa were expressed on the cell surface and were recognized by a well-characterized panel of murine and human monoclonal and polyclonal antibodies. Like Pena, the Penb form of GPIIb-IIIa could undergo conformational changes in response to RGD peptide binding, and could be induced by activating antibodies to bind Fg and the Fg mimetic antibody P1-55. The binding affinity for Fg of the Pena form of the GPIIb-IIIa complex was not significantly different from that of the Penb form, nor was its ability to signal to focal adhesion kinase, suggesting that Arg143Gln polymorphism has little or no effect on integrin function. Examination of the functional consequences of other integrin polymorphisms may be necessary to determine whether they constitute a risk factor for thrombosis or hemorrhage.
authors.affiliation: Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA. rwang@smtpgate.bcsew.edu
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: P J
authors.initials: PJ
authors.lastname: Newman
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D016824:Antigens, Human Platelet / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001665:Binding Sites; D016466:CHO Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005340:Fibrinogen / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C057260:4a alloantigen, human; C510800:4b alloantigen, human; D016824:Antigens, Human Platelet; D015815:Cell Adhesion Molecules; D008024:Ligands; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011993:Recombinant Fusion Proteins; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human