Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor

Journal Article · Mon Apr 01 04:00:00 EST 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.7.2946· OSTI ID:5029954

Ware, J; Dent, J A; Azuma, Hiroyuki; Sugimoto, Mitsuhiko; Kyrle, P A; Yoshioka, Akira; Ruggeri, Z M ^[1]

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1. Research Inst. of Scripps Clinic, La Jolla, CA (United States)

von Willebrand factor (vWF) supports platelet adhesion on thrombogenic surfaces by binding to platelet membrane glycoprotein (GP) Ib in the GP Ib-IX receptor complex. This interaction is physiologically regulated so that it does not occur between circulating vWF and platelets but, rather, only at a site of vascular injury. The abnormal vWF found in type IIB von Willebrand disease, however, has a characteristically increased affinity for GP Ib and binds to circulating platelets. The authors have analyzed the molecular basis of this abnormality by sequence analysis of a type IIB vWF cDNA and have identified a single amino acid change, Trp{sup 550} to Cys{sup 550}, located in the GP IB-binding domain of the molecule comprising residues 449-728. Bacterial expression of recombinant fragments corresponding to this vWF domain yielded molecules that, whether containing a normal Trp{sup 550} or a mutant Cys{sup 550} residue, bound directly to GP Ib in the absence of modulators and with similar affinity. These results identify a region of vWF that, although not thought to be directly involved in binding to GP Ib, may modulate the interaction through conformational changes.

• OSTI ID: 5029954
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Journal Issue: 7 Vol. 88:7; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
ADHESION
AUTORADIOGRAPHY
BETA DECAY RADIOISOTOPES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BLOOD PLATELETS
BODY FLUIDS
CARDIOVASCULAR DISEASES
CHROMATOGRAPHY
DAYS LIVING RADIOISOTOPES
DISEASES
DNA
DNA SEQUENCING
ELECTRON CAPTURE RADIOISOTOPES
ETIOLOGY
GENE MUTATIONS
GLYCOPROTEINS
HEREDITARY DISEASES
INTERMEDIATE MASS NUCLEI
INTERNAL CONVERSION RADIOISOTOPES
IODINE 125
IODINE ISOTOPES
ION EXCHANGE CHROMATOGRAPHY
ISOTOPES
MATERIALS
MEMBRANE PROTEINS
MUTATIONS
NUCLEI
NUCLEIC ACIDS
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
PROTEINS
RADIOISOTOPES
RECEPTORS
RECOMBINANT DNA
SEPARATION PROCESSES
STRUCTURAL CHEMICAL ANALYSIS
THROMBOSIS
VASCULAR DISEASES