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Thromb Haemost 2002; 87(02): 329-333
DOI: 10.1055/s-0037-1612994
Letters to the Editor
Schattauer GmbH

Molecular Modeling of the Seven Tandem Leucine-Rich Repeats within the Ligand-Binding Region of Platelet Glycoprotein Ibα

James C. Whisstock
1   The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
,
Yang Shen
1   The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
2   Hazel and Pip Appel Vascular Biology Laboratory, Baker Medical Research Institute, Melbourne, Australia
,
José A. López
3   Department of Medicine and Department of Molecular and Human Genetics, Baylor College of Medicine
4   Veterans Affairs Medical Center, Houston, Texas, USA
,
Robert K. Andrews
1   The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
2   Hazel and Pip Appel Vascular Biology Laboratory, Baker Medical Research Institute, Melbourne, Australia
,
Michael C. Berndt
1   The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
2   Hazel and Pip Appel Vascular Biology Laboratory, Baker Medical Research Institute, Melbourne, Australia
3   Department of Medicine and Department of Molecular and Human Genetics, Baylor College of Medicine
› Author Affiliations
Further Information

Publication History

Received 26 June 2001

Accepted after revision 15 October 2001

Publication Date:
13 December 2017 (online)

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Summary

Platelet glycoprotein (GP)Ib-IX-V mediates von Willebrand Factor (vWF)-dependent adhesion to vascular subendothelium at high shear in (patho)physiological thrombus formation. The ligand-binding domain of GPIb-IX-V is within the N-terminal 282 residues of GPIbα, that contains seven tandem leucine-rich repeats (Leu36–Ala200). Repeats 2–4 are critical for vWF binding. In this study, we have built molecular models of the seven leucine-rich repeats of human, canine and mouse GPIbα, providing novel insights into the species-specific interaction between human vWF and its receptor. Interestingly, a major difference between the models was a large negatively charged patch on the concave face of human, but not canine, repeats 2–4. In addition, five individual mutations within the leucine-rich repeats of GPIbα associated with the bleeding disorder Bernard-Soulier syndrome, that result in dysfunctional vWF binding, were mapped to the model of human GPIbα. This provides the basis for relating these genetic lesions to abnormal function of the receptor.

Keywords

Glycoprotein Ibα - platelets - leucine-rich repeats - Bernard-Soulier syndrome
 

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