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首页> 外文期刊>Molecular and Cellular Biology >Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction.
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Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction.

机译：TYK2结合和信号转导所需的α干扰素受体1亚基（IFNaR1）域的分子表征。

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Binding of alpha interferon (IFNalpha) to its receptors induces rapid tyrosine phosphorylation of the receptor subunits IFNaR1 and IFNaR2, the TYK2 and JAK1 tyrosine kinases, and the Stat1 and Stat2 transcription factors. Previous studies have demonstrated that TYK2 directly and specifically binds to and tyrosine phosphorylates IFNaR1 in vitro. We now report a detailed analysis of the TYK2 binding domain on the IFNaR1 subunit. First, we used an in vitro binding assay to identify the TYK2 binding motif in IFNaR1 as well as the critical residues within this region. The most striking feature is the importance of a number of hydrophobic and acidic residues. A minor role is also ascribed to a region resembling the proline-rich "box 1" sequence. In addition, mutations which disrupt in vitro binding also disrupt the coimmunoprecipitation of the receptor and TYK2. We also provide direct evidence that the binding region is both necessary and sufficient to activate TYK2 in vivo. Specifically, mutations in the binding domain act in a dominant-negative fashion to inhibit the IFNalpha-induced tyrosine phosphorylation of TYK2 and Stat2. Further, introduction of dimerized glutathione S-transferase-IFNaR1 fusion proteins into permeabilized cells is sufficient to induce phosphorylation of TYK2 and the receptor, confirming the role of the binding domain in IFNalpha signal transduction. These studies provide clues to the sequences determining the specificity of the association between JAK family tyrosine kinases and cytokine receptors as well as the functional role of these kinases in cytokine signal transduction.
机译：α干扰素（IFNalpha）与其受体的结合诱导受体亚基IFNaR1和IFNaR2，TYK2和JAK1酪氨酸激酶以及Stat1和Stat2转录因子的酪氨酸快速磷酸化。先前的研究表明，TYK2在体外直接和特异性结合并酪氨酸磷酸化IFNaR1。现在，我们报告IFNaR1亚基上TYK2结合域的详细分析。首先，我们使用体外结合试验来确定IFNaR1中的TYK2结合基序以及该区域内的关键残基。最显着的特征是许多疏水和酸性残基的重要性。次要作用也归因于类似于富含脯氨酸的“框1”序列的区域。另外，破坏体外结合的突变也破坏了受体和TYK2的共免疫沉淀。我们还提供了直接的证据，证明该结合区域在体内激活TYK2既必要又足够。具体而言，结合域中的突变以显性负性方式起作用，以抑制IFNα诱导的TYK2和Stat2酪氨酸磷酸化。此外，将二聚的谷胱甘肽S-转移酶-IFNaR1融合蛋白引入通透性细胞中足以诱导TYK2和受体的磷酸化，从而确认结合域在IFNα信号转导中的作用。这些研究为确定JAK家族酪氨酸激酶和细胞因子受体之间的关联的特异性的序列以及这些激酶在细胞因子信号转导中的功能作用提供了线索。

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