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首页> 外文期刊>Biochemistry >Activation of individual alpha IIb beta 3 integrin molecules by disruption of transmembrane domain interactions in the absence of clustering
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Activation of individual alpha IIb beta 3 integrin molecules by disruption of transmembrane domain interactions in the absence of clustering

机译：在没有聚类的情况下通过破坏跨膜结构域相互作用来激活单个αIIbβ3整联蛋白分子

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We used laser tweezers-based force spectroscopy to measure the binding strength between fibrinogen molecules covalently bound to latex beads and either wild-type alpha IIb beta 3 molecules or alpha IIb beta 3 molecules containing the transmembrane domain mutations beta 3 G708N or alpha IIb G972N expressed on Chinese hamster ovary cells. As we demonstrated previously for alpha II beta 3 on agonist-stimulated platelets and for purified alpha IIb beta 3 molecules incubated with Mn2+, two regirnes of rupture forces were present when wild-type alpha IIb beta 3 was activated by the monoclonal antibody PT25-2: rupture forces of 20-60 pN with an exponentially decreasing probability of detection and rupture forces in the range of 60-150 pN with a maximum at similar to 70-80 pN. Both rupture force regimes were specific for fibrinogen binding to the activated conformation of alpha IIb beta 3 because they were inhibited by alpha IIb beta 3-specific antagonists. Identical rupture force regimes were present constitutively when cells expressing the alpha IIb and beta 3 transmembrane domain mutants were studied, confirming that these mutations induced an active alpha IIb beta 3 conformation. Moreover, there were no significant differences in the yield strength of the low-to-moderate and strong force regimes when alpha IIb beta 3 was activated by PT25-2 or the transmembrane domain mutations, implying that there was no fundamental difference in the way these forms of activated alpha IIb beta 3 interacted with fibrinogen. Thus, the two-step pathway of the interaction of alpha IIb beta 3 with fibrinogen we have identified appears to be a fundamental property of the high-affinity state of alpha IIb beta 3 and is identical regardless of whether this affinity state is achieved by intracellular, extracellular, or membrane-associated events.
机译：我们使用基于激光镊子的力谱来测量与乳胶珠共价结合的纤维蛋白原分子与野生型αIIb beta 3分子或包含跨膜结构域突变beta 3 G708N或alpha IIb G972N表达的alpha IIb beta 3分子之间的结合强度在中国仓鼠卵巢细胞上。正如我们先前针对激动剂刺激的血小板上的αII beta 3和与Mn2 +孵育的纯化的αIIb beta 3分子所证明的那样，当野生型αIIb beta 3被单克隆抗体PT25-2激活时，存在两个断裂力作用域。 ：破裂力为20-60 pN，检测和破裂力的概率呈指数下降，范围为60-150 pN，最大值类似于70-80 pN。两种断裂力方案都对血纤蛋白原与αIIb beta 3的激活构象具有特异性，因为它们均受到αIIb beta 3特异性拮抗剂的抑制。当研究表达αIIb和β3跨膜结构域突变体的细胞时，组成性存在相同的断裂力机制，从而证实这些突变诱导了活跃的αIIbβ3构象。此外，当αIIb beta 3被PT25-2激活或跨膜结构域突变激活时，低至中力和强力作用方式的屈服强度没有显着差异，这表明这些方式没有根本差异。形式的活化αIIbβ3与纤维蛋白原相互作用。因此，我们已经确定的αIIb beta 3与纤维蛋白原相互作用的两步途径似乎是αIIb beta 3高亲和力状态的基本性质，并且无论该亲和力状态是否通过细胞内达到，它都是相同的，细胞外或膜相关事件。

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