title: Polymorphism of human glycoprotein Ib alpha results from a variable number of tandem repeats of a 13-amino acid sequence in the mucin-like macroglycopeptide region. Structure/function implications.
abstract: Four polymorphic variants of the platelet receptor for von Willebrand factor, glycoprotein Ib, have been described that differ in molecular weight on sodium dodecyl sulfate-polyacrylamide gels (Moroi, M., Jung, S. M., and Yoshida, N. (1984) Blood 64, 622-629). A recent report localized the polymorphic site to the heavily O-glycosylated region of the glycoprotein Ib alpha-chain known as the macroglycopeptide (Meyer, M., and Schellenberg, I. (1990) Thromb. Res. 58, 233-242). This region contains several tandem repeats of a mucin-like sequence, which appeared to be a likely site for polymorphic variation. We amplified genomic DNA corresponding to the macroglycopeptide from 206 individuals from four ethnic groups and identified three length variants based on the migration of the amplified DNA on denaturing polyacrylamide gels. DNA sequencing revealed that the three variants represented four alleles, two of which varied by only one base pair, a difference that did not result in an amino acid change. The three length variants differed in the number of tandem repeats of a 39-base pair sequence that results in perfect duplication of a 13-amino acid sequence that originated within a region flanked by Glu-396 and Thr-411. The smallest isoform contained one such sequence; the next largest, two repeats; and the largest, three repeats. The DNA sequence containing the tandem repeats was flanked by direct repeats typical of the target site duplications found flanking transposed DNA, suggesting a mechanism for acquisition of this region by the primordial glycoprotein Ib alpha precursor. The amino acid sequence of the repeated element that accounts for the polymorphism contained five sites for potential O-glycosylation, which together with the repeated amino acids would result in incremental differences in molecular weight of approximately 6,000 between the different isoforms. The addition of repeats to the macroglycopeptide is predicted to increase the length of this elongated glycosylated region and extend the distance between the ligand-binding domain of glycoprotein Ib and the platelet plasma membrane, an effect that would project the ligand-binding domain farther into the bloodstream. Such a change may alter the susceptibility of platelets to shear-induced activation, a process that requires an interaction between glycoprotein Ib and von Willebrand factor.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California.
authors.forename: J A
authors.initials: JA
authors.lastname: López
authors.forename: E H
authors.initials: EH
authors.lastname: Ludwig
authors.forename: B J
authors.initials: BJ
authors.lastname: McCarthy
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005006:Ethnicity; D014644:Genetic Variation; D005838:Genotype; D006020:Glycopeptides; D006239:Haplotypes; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D008969:Molecular Sequence Data; D009077:Mucins / Q000235:genetics; D009838:Oligodeoxyribonucleotides; D010980:Platelet Membrane Glycoproteins / Q000235:genetics* / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D044469:Racial Groups; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D006020:Glycopeptides; D009077:Mucins; D009838:Oligodeoxyribonucleotides; D010980:Platelet Membrane Glycoproteins; D004247:DNA