Regulation of integrin αIIbβ3, 3 activation by distinct regions of its cytoplasmic tails
Regulation of integrin αIIbβ3, 3 activation by distinct regions of its cytoplasmic tails
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DOI：
10.1021/bi060279h
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发表时间：
2006-05-30
期刊：
影响因子：
2.9
通讯作者：
Plow, Edward F.
中科院分区：
文献类型：
--
作者：
Ma, Yan-Qing;Yang, Jun;Plow, Edward F.
短胞质尾通过其近膜螺旋的扣紧/松开来调节整合素粘附受体的激活。使用整合素 R-IIb beta(3) 作为模型，我们发现先前报道的激活突变 α(IIb)((RD)-D-995) 扰乱了扣环中的静电界面，仅部分激活了 α(IIb)beta(3)，并且通过完全删除 α(IIb) CT 或三重突变来实现受体的广泛激活。 α(IIb)(V(990)A/F(992)A/(RD)-D-995) 破坏扣环中的静电和疏水界面。结果为基于平衡的整合素激活过程提供了定量证据，其中将平衡转变为完全激活状态需要完全松开细胞质尾部。我们进一步证明，虽然 alpha(IIb) 尾部的 C 端区域对 alpha(IIb)beta(3) 激活的影响最小，但 beta(3) 尾部的 C 端区域至关重要。该区域中 (SP)-P-752 的致病突变（而非 S(752)A）抑制了 (RD)-D-995 或 talin 头结构域诱导的部分激活，但不影响 α(IIb) 截短诱导的激活。 NMR 光谱显示 (SP)-P-752 但不是 S(752)A 突变破坏了 β(3) 尾内的 C 末端螺旋，表明 C 末端螺旋可能调节基于平衡的扣紧/松开过程。总之，这些数据提供了关于细胞质尾部的不同区域如何差异和协同调节整合素激活的分子见解。
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.