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首页> 外文期刊>Journal of Molecular Biology >Interaction Analyses of 14-3-3ζ, Dok1, and Phosphorylated Integrin β Cytoplasmic Tails Reveal a Bi-molecular Switch in Integrin Regulation
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Interaction Analyses of 14-3-3ζ, Dok1, and Phosphorylated Integrin β Cytoplasmic Tails Reveal a Bi-molecular Switch in Integrin Regulation

机译：14-3-3℃，DOK1和磷酸化整合蛋白β细胞质尾部的相互作用分析显示整合素调节的双分子开关

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摘要

Integrins are hetero-dimeric (α and β subunits) type I transmembrane proteins that facilitate cell adhesion and migration. The cytoplasmic tails (CTs) of integrins interact with a plethora of intra-cellular proteins that are required for integrin bidirectional signaling. In particular, the β CTs of integrins are known to recruit a variety of cytosolic proteins that often have overlapping recognition sites. However, the chronological sequence of β CTs/cytosolic proteins interactions remains to be fully characterized. Previous studies have shown that the scaffold protein 14-3-3ζ binds to phosphorylated β CTs in activated integrins, whereas interactions of Dok-1 with phosphorylated β CTs maintained integrins in the resting state. In this study, we examined the binding interactions between 14-3-3ζ, Dok1, and phosphorylated integrin β2 and β3 CTs. We show that the scaffold protein 14-3-3ζ interacts with the phosphotyrosine binding (PTB) domain of Dok1 even in the absence of the phosphorylated integrin β CTs. The interactions were mapped onto the β-sheet region of the PTB domain of Dok1. Furthermore, we provide evidence that the 14-3-3ζ/Dok1 binary complex is able to bind to their cognate phosphorylated sequence motifs in the integrin β CTs. We demonstrate that Thr phosphorylated pTTT β2 CT or pTST β3 CT can bind to 14-3-3ζ that is in complex with the Dok1 PTB domain, whereas Ser phosphorylated β2 CT or Tyr phosphorylated β3 CT interacted with Dok1 in 14-3-3ζ/Dok1 complex. Based on these data, we propose that 14-3-3ζ/Dok1 complex could serve as a molecular switch providing novel molecular insights into the regulating integrin activation.
机译：整联蛋白是杂种二聚体（α和β亚基）I型跨膜蛋白，其促进细胞粘附和迁移。整联蛋白的细胞质尾（CTS）与整合蛋白双向信号传导所需的多种细胞内蛋白质相互作用。特别地，已知整合蛋白的βCTS募集通常具有重叠识别位点的各种细胞溶胶蛋白。然而，βCTS/胞嘧啶蛋白相互作用的时间顺序仍有待完全表征。以前的研究表明，支架蛋白14-3-3ζ与活化的整年蛋白中的磷酸化βCTS结合，而DOK-1与磷酸化βCTS的相互作用保持在静止状态下的整数。在这项研究中，我们检查了14-3-3℃，DoK1和磷酸化整合蛋白β2和β3CTS之间的结合相互作用。我们表明支架蛋白14-3-3ζ即使在没有磷酸化的整联蛋白βCTS的情况下，也与DOK1的磷酸酪氨酸结合（PTB）结构域相互作用。将相互作用映射到DOK1的PTB结构域的β-片状区域上。此外，我们提供了证据表明14-3-3ζ/ dok1二元复合物能够与其在整联蛋白βCTS中的同源磷酸化序列基序结合。我们证明THR磷酸化的PTTTβ2CT或PTSTβ3CT可以结合14-3-3×，与DOK1 PTB结构域复合，而SER磷酸化β2CT或TYR磷酸化β3CT与DOK1相互作用/ dok1复杂。基于这些数据，我们提出14-3-3×10K1复合物可以用作分子开关，为调节整合素激活提供新的分子见解。

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