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

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

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 results 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.

Original languageEnglish
Pages (from-to)329-333
Number of pages5
JournalThrombosis and Haemostasis
Volume87
Issue number2
Publication statusPublished - 21 Feb 2002

Keywords

  • Bernard-Soulier syndrome
  • Glycoprotein Ibα
  • Leucine-rich repeats
  • Platelets

Cite this

@article{733e3313047849f29ae6ce42385cf60e,
title = "Molecular modeling of the seven tandem leucine-rich repeats within the ligand-binding region of platelet glycoprotein Ibα",
abstract = "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 results 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 = "Bernard-Soulier syndrome, Glycoprotein Ibα, Leucine-rich repeats, Platelets",
author = "Whisstock, {James C.} and Yang Shen and L{\'o}pez, {Jos{\'e} A.} and Andrews, {Robert K.} and Berndt, {Michael C.}",
year = "2002",
month = "2",
day = "21",
language = "English",
volume = "87",
pages = "329--333",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "Schattauer",
number = "2",

}

Molecular modeling of the seven tandem leucine-rich repeats within the ligand-binding region of platelet glycoprotein Ibα. / Whisstock, James C.; Shen, Yang; López, José A.; Andrews, Robert K.; Berndt, Michael C.

In: Thrombosis and Haemostasis, Vol. 87, No. 2, 21.02.2002, p. 329-333.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Molecular modeling of the seven tandem leucine-rich repeats within the ligand-binding region of platelet glycoprotein Ibα

AU - Whisstock, James C.

AU - Shen, Yang

AU - López, José A.

AU - Andrews, Robert K.

AU - Berndt, Michael C.

PY - 2002/2/21

Y1 - 2002/2/21

N2 - 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 results 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.

AB - 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 results 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.

KW - Bernard-Soulier syndrome

KW - Glycoprotein Ibα

KW - Leucine-rich repeats

KW - Platelets

UR - http://www.scopus.com/inward/record.url?scp=0036172516&partnerID=8YFLogxK

M3 - Article

VL - 87

SP - 329

EP - 333

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 2

ER -