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

James C. Whisstock; Yang Shen; José A. López; Robert K. Andrews; Michael C. Berndt

doi:10.1055/s-0037-1612994

Thrombosis and Haemostasis, Table of Contents

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

¹The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

,

Yang Shen

¹The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

²Hazel and Pip Appel Vascular Biology Laboratory, Baker Medical Research Institute, Melbourne, Australia

,

José A. López

³Department of Medicine and Department of Molecular and Human Genetics, Baylor College of Medicine

⁴Veterans Affairs Medical Center, Houston, Texas, USA

,

Robert K. Andrews

¹The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

²Hazel and Pip Appel Vascular Biology Laboratory, Baker Medical Research Institute, Melbourne, Australia

,

Michael C. Berndt

¹The Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

²Hazel and Pip Appel Vascular Biology Laboratory, Baker Medical Research Institute, Melbourne, Australia

³Department of Medicine and Department of Molecular and Human Genetics, Baylor College of Medicine

› Author Affiliations

Abstract

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

Full Text

References

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