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首页> 外文期刊>Biochemistry >Regulation of integrin alpha(IIb)beta(3), 3 activation by distinct regions of its cytoplasmic tails
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Regulation of integrin alpha(IIb)beta(3), 3 activation by distinct regions of its cytoplasmic tails

机译：整联蛋白α（IIb）beta（3），3通过其胞质尾巴的不同区域的激活的调节

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摘要

The short cytoplasmic tails regulate activation of integrin adhesion receptors via clasping/ unclasping of their membrane-proximal helices. Using integrin R-IIb beta(3) as a model, we show that a previously reported activating mutation alpha(IIb)((RD)-D-995) that perturbs the electrostatic interface in the clasp only partially activates alpha(IIb)beta(3) and that extensive activation of the receptor is achieved by complete deletion of alpha(IIb) CT or triple mutations in alpha(IIb)(V(990)A/F(992)A/(RD)-D-995) that disrupt both electrostatic and hydrophobic interfaces in the clasp. The results provide quantitative evidence for an equilibrium-based integrin activation process where shifting the equilibrium to the fully activated state requires total unclasping of the cytoplasmic tails. We further demonstrate that while the C-terminal region of the alpha(IIb) tail minimally influences alpha(IIb)beta(3) activation, the C-terminal region of the beta(3) tail is critically involved. A disease-causing mutation of (SP)-P-752 in this region, but not S(752)A, suppressed partial activation induced by (RD)-D-995 or the talin head domain but did not affect activation induced by alpha(IIb) truncation. NMR spectroscopy revealed that (SP)-P-752 but not the S(752)A mutation disrupted a C-terminal helix within the beta(3) tail, suggesting that the C-terminal helix may regulate the equilibrium-based clasping/unclasping process. Together, these data provide molecular insights into how distinct regions of the cytoplasmic tails differentially and cooperatively regulate integrin activation.
机译：短的胞质尾巴通过扣紧/解开其膜近端螺旋来调节整联蛋白粘附受体的活化。使用整联蛋白R IIb beta（3）作为模型，我们显示了先前报道的扰动扣环中静电界面的激活突变alpha（IIb）（（RD）-D-995）仅部分激活了alpha（IIb）beta （3）并且受体的广泛激活是通过完全删除alpha（IIb）CT或alpha（IIb）（V（990）A / F（992）A /（RD）-D-995）中的三重突变来实现的会破坏表扣中的静电和疏水界面。结果为基于平衡的整联蛋白活化过程提供了定量证据，其中将平衡转移到完全活化状态需要完全解吸胞质尾巴。我们进一步证明，尽管alpha（IIb）尾部的C末端区域对alpha（IIb）beta（3）激活的影响最小，但beta（3）尾部的C末端区域却受到严重影响。该区域的（SP）-P-752致病突变而非S（752）A抑制了（RD）-D-995或塔林头部结构域诱导的部分活化，但不影响α诱导的活化（IIb）截断。 NMR光谱显示（SP）-P-752而不是S（752）A突变破坏了beta（3）尾巴内的C末端螺旋，表明C末端螺旋可能调节基于平衡的扣紧/解扣处理。在一起，这些数据提供了分子见解，以了解胞质尾巴的不同区域如何差异地和协同地调节整联蛋白的活化。

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