Conformational energy analysis of the substitution of Val for Gly 233 in a functional region of platelet GPIbα in platelet-type von Willebrand disease

Matthew R. Pincus, Daryll C. Dykes, Robert P. Carty, Jonathan L. Miller

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder in which patient platelets exhibit an abnormally increased binding of circulating von Willebrand factor (vWF). We have recently shown that this abnormality is associated with a point mutation resulting in substitution of Val for Gly 233 in platelet membrane glycoprotein Ibα (GPIbga), a major component of the platelet (GPIb/IX receptor for vWF. To investigate the effect of this substitution on the three-dimensional structure of this region of the protein, we have generated the allowed (low energy) conformations of the region of the GPIα protein containing residues 228-238 (with 5 residues on either side of the critical residue 233) with Gly 233 (wild type) and Val 233 (PT-vWD) using the computer program ECEPP (Empirical Conformational Energies of Peptides Program). The wild-type sequence is Tyr-Val-Trp-Lys-Gln-Gly-Val-Asp-Val-Lys-Ala. We find that the Gly 233-containing peptide can exist in two low energy conformers. The lowest energy conformer is a structure containing a β-turn at Gln 232-Gly 233 while the alternative conformation is an amphipathic helical structure. Only the amphipathic helical structure is allowed for the Val 233-containing peptide which contains a hydrophobic 'face' consisting of Val 229, Val 233 and Val 236 and another hydrophilic surface composed of such residues as Lys 231 and Asp 235. No such surfaces exist for the lowest energy bend conformer for the Gly 233-containing peptide, but do exist in the higher energy helical structure. The amphiphatic surfaces in the 228-238 region of the Val 233-containing GPIbα protein may associate strongly with complementary surfaces during vWF binding to the GPIb/IX receptor complex and may help explain heightened association of vWF with this receptor in PT-vWD.

Original languageEnglish
Pages (from-to)133-139
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1097
Issue number2
DOIs
StatePublished - 23 Sep 1991
Externally publishedYes

Keywords

  • Amphipathic structure
  • GPIbα protein
  • Peptide segment
  • Platelet aggregation
  • Platelet-type von Willebrand disease
  • Von Willebrand Factor Conformational energy

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