Requirement of leucine-rich repeats of glycoprotein (GP) Ibα for shear- dependent and static binding of von willebrand factor to the platelet membrane GP Ib-IX-V complex

Yang Shen, Gabriel M. Romo, Jing Fei Dong, Alicia Schade, Larry V. McIntire, Dermot Kenny, James C. Whisstock, Michael C. Berndt, José A. López, Robert K. Andrews

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Abstract

The platelet glycoprotein (GP) Ib-IX-V complex mediates adhesion to von Willebrand factor (vWf) in (patho)physiologic thrombus formation. The vWf- binding site on GP Ib-IX-V is within the N-terminal 282 residues of GP Ibα, which consist of an N-terminal flanking sequence (His-1-IIe-35), 7 leucine- rich repeats (Leu-36-Ala200), a C-terminal flank (Phe-201-Gly268), and a sulfated tyrosine sequence (Asp-269-Glu-282). We have used mammalian cell expression of canine-human chimeras of GP Ibα, corresponding to precise structural boundaries, to demonstrate the first specific requirement for individual leucine-rich repeats for binding of vWf either induced by a modulator, ristocetin, or under hydrodynamic flow. Implicit in this approach was that the GP Ibα chimeras retained a functional conformation, a supposition confirmed by analyzing restoration of function to reversed human- canine chimeras and demonstrating that all chimeras bound vWf activated by botrocetin, a modulator that is indiscriminate between species. Leucine-rich repeats 2, 3, and 4 of GP Ibα were identified as being critical for vWf adhesion to GP Ib-IX-V.

Original languageEnglish
Pages (from-to)903-910
Number of pages8
JournalBlood
Volume95
Issue number3
Publication statusPublished - 1 Feb 2000

Cite this

Shen, Yang ; Romo, Gabriel M. ; Dong, Jing Fei ; Schade, Alicia ; McIntire, Larry V. ; Kenny, Dermot ; Whisstock, James C. ; Berndt, Michael C. ; López, José A. ; Andrews, Robert K. / Requirement of leucine-rich repeats of glycoprotein (GP) Ibα for shear- dependent and static binding of von willebrand factor to the platelet membrane GP Ib-IX-V complex. In: Blood. 2000 ; Vol. 95, No. 3. pp. 903-910.
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abstract = "The platelet glycoprotein (GP) Ib-IX-V complex mediates adhesion to von Willebrand factor (vWf) in (patho)physiologic thrombus formation. The vWf- binding site on GP Ib-IX-V is within the N-terminal 282 residues of GP Ibα, which consist of an N-terminal flanking sequence (His-1-IIe-35), 7 leucine- rich repeats (Leu-36-Ala200), a C-terminal flank (Phe-201-Gly268), and a sulfated tyrosine sequence (Asp-269-Glu-282). We have used mammalian cell expression of canine-human chimeras of GP Ibα, corresponding to precise structural boundaries, to demonstrate the first specific requirement for individual leucine-rich repeats for binding of vWf either induced by a modulator, ristocetin, or under hydrodynamic flow. Implicit in this approach was that the GP Ibα chimeras retained a functional conformation, a supposition confirmed by analyzing restoration of function to reversed human- canine chimeras and demonstrating that all chimeras bound vWf activated by botrocetin, a modulator that is indiscriminate between species. Leucine-rich repeats 2, 3, and 4 of GP Ibα were identified as being critical for vWf adhesion to GP Ib-IX-V.",
author = "Yang Shen and Romo, {Gabriel M.} and Dong, {Jing Fei} and Alicia Schade and McIntire, {Larry V.} and Dermot Kenny and Whisstock, {James C.} and Berndt, {Michael C.} and L{\'o}pez, {Jos{\'e} A.} and Andrews, {Robert K.}",
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Requirement of leucine-rich repeats of glycoprotein (GP) Ibα for shear- dependent and static binding of von willebrand factor to the platelet membrane GP Ib-IX-V complex. / Shen, Yang; Romo, Gabriel M.; Dong, Jing Fei; Schade, Alicia; McIntire, Larry V.; Kenny, Dermot; Whisstock, James C.; Berndt, Michael C.; López, José A.; Andrews, Robert K.

In: Blood, Vol. 95, No. 3, 01.02.2000, p. 903-910.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Shen, Yang

AU - Romo, Gabriel M.

AU - Dong, Jing Fei

AU - Schade, Alicia

AU - McIntire, Larry V.

AU - Kenny, Dermot

AU - Whisstock, James C.

AU - Berndt, Michael C.

AU - López, José A.

AU - Andrews, Robert K.

PY - 2000/2/1

Y1 - 2000/2/1

N2 - The platelet glycoprotein (GP) Ib-IX-V complex mediates adhesion to von Willebrand factor (vWf) in (patho)physiologic thrombus formation. The vWf- binding site on GP Ib-IX-V is within the N-terminal 282 residues of GP Ibα, which consist of an N-terminal flanking sequence (His-1-IIe-35), 7 leucine- rich repeats (Leu-36-Ala200), a C-terminal flank (Phe-201-Gly268), and a sulfated tyrosine sequence (Asp-269-Glu-282). We have used mammalian cell expression of canine-human chimeras of GP Ibα, corresponding to precise structural boundaries, to demonstrate the first specific requirement for individual leucine-rich repeats for binding of vWf either induced by a modulator, ristocetin, or under hydrodynamic flow. Implicit in this approach was that the GP Ibα chimeras retained a functional conformation, a supposition confirmed by analyzing restoration of function to reversed human- canine chimeras and demonstrating that all chimeras bound vWf activated by botrocetin, a modulator that is indiscriminate between species. Leucine-rich repeats 2, 3, and 4 of GP Ibα were identified as being critical for vWf adhesion to GP Ib-IX-V.

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