The Structural Basis for Class II Cytokine Receptor Recognition by JAK1.
The Structural Basis for Class II Cytokine Receptor Recognition by JAK1.
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DOI：
10.1016/j.str.2016.03.023
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发表时间：
2016-06-07
期刊：
影响因子：
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通讯作者：
Lupardus PJ
中科院分区：
文献类型：
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作者：
Ferrao R;Wallweber HJ;Ho H;Tam C;Franke Y;Quinn J;Lupardus PJ
JAK 1是Janus激酶（JAK）家族的非受体酪氨酸激酶的成员，其响应于细胞因子和干扰素而被激活。在这里，我们提出了两个晶体结构的人JAK 1 FERM和SH 2结构域结合的肽衍生自II类细胞因子受体IFN-λ受体1和IL-10受体1（IFNLR 1和IL-10 RA）。这些结构揭示了JAK 1 FERM中的相互作用位点，其容纳所谓的“box 1”近膜受体肽基序。JAK 1-IFNLR 1相互作用的生物物理分析表明，受体盒1是JAK 1相互作用的主要驱动因素，并确定了II类受体中保守的残基对结合很重要。此外，我们证明了第二个“box 2”受体基序进一步稳定JAK 1-IFNLR 1复合物。总之，这些数据确定了一个保守的JAK结合位点的受体肽，并阐明了II类细胞因子受体与JAK 1相互作用的机制。细胞因子受体盒1基序对于JAK激酶结合和激活至关重要。Ferrao等人揭示了来自II类细胞因子受体IFNLR 1和IL 10 RA的box 1的结构，其结合到人JAK 1的FERM-SH 2结构域，鉴定了JAK 1相互作用的共有基序。
JAK1 is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases that are activated in response to cytokines and interferons. Here we present two crystal structures of the human JAK1 FERM and SH2 domains bound to peptides derived from the class II cytokine receptors IFN-λ receptor 1 and IL-10 receptor 1 (IFNLR1 and IL10RA). These structures reveal an interaction site in the JAK1 FERM that accommodates the so-called “box1” membrane-proximal receptor peptide motif. Biophysical analysis of the JAK1–IFNLR1 interaction indicates that the receptor box1 is the primary driver of the JAK1 interaction, and identifies residues conserved among class II receptors as important for binding. In addition, we demonstrate that a second “box2” receptor motif further stabilizes the JAK1–IFNLR1 complex. Together, these data identify a conserved JAK binding site for receptor peptides and elucidate the mechanism by which class II cytokine receptors interact with JAK1. The cytokine receptor box1 motif is critical for JAK kinase binding and activation. Ferrao et al. reveal the structure of box1 from class II cytokine receptors IFNLR1 and IL10RA bound to the FERM-SH2 domain of human JAK1, identifying a consensus motif for JAK1 interaction.