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
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
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DOI：
10.1182/blood.v95.3.903.003k37_903_910
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发表时间：
2000-02-01
期刊：
影响因子：
20.3
通讯作者：
Andrews, RK
中科院分区：
文献类型：
--
作者：
Shen, Y;Romo, GM;Andrews, RK
血小板糖蛋白（GP）Ib-IX-V复合物在（病理）生理性血栓形成中介导与血管性血友病因子（vWf）的粘附。GP Ib-IX-V上的vWf结合位点位于GP Iba的N端282个残基内，其由N端侧翼序列组成（His-1-IIe-35），7个富含亮氨酸的重复序列（Leu-36-Ala-200），C末端侧翼（Phe-201-Gly-268）和硫酸化酪氨酸序列（Asp-269-Glu-282），我们使用了GP Ib α的犬-人嵌合体的哺乳动物细胞表达，对应于精确的结构边界，以证明第一个特定的要求，个别富含亮氨酸的重复结合vWf无论是由一个调节剂，利托那肽，或在流体动力学流动。该方法中隐含的是GP Ib α嵌合体保留了功能性构象，这是通过分析逆转的人-犬嵌合体的功能恢复并证明所有嵌合体结合由肉毒素（一种在物种之间不加区别的调节剂）激活的vWf而证实的假设。GP Ib α的富含亮氨酸的重复序列2、3和4被确定为vWf粘附至GP Ib-IX-V的关键。(C)2000年，美国血液学会。
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 Iba, which consist of an N-terminal flanking sequence (His-1-IIe-35), 7 leucine-rich repeats (Leu-36-Ala-200), a C-terminal flank (Phe-201-Gly-268), and a sulfated tyrosine sequence (Asp-269-Glu-282), We have used mammalian cell expression of canine-human chimeras of GP Ib alpha, 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 Ib alpha 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 Ib alpha were identified as being critical for vWf adhesion to GP Ib-IX-V.(C) 2000 by The American Society of Hematology.