Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling.

细胞因子信号传导抑制因子 (SOCS)2 蛋白是生长激素 (GH) 和 Janus 激酶 (JAK) 信号转导和转录激活因子 (STAT) 信号级联的关键负调节因子。中心 SOCS2-Src 同源 2 (SH2) 结构域是 SOCS 家族蛋白的特征，是促进识别带有磷酸化酪氨酸 (pTyr) 残基的靶标的重要模块。在这里，我们鉴定了 SOCS2-SH2 结构域上的一个外部位点，当与非磷酸化肽 (F3) 结合时，该外部位点会增强 SH2 对经典磷酸化配体的亲和力。 SOCS2/F3 晶体结构的解表明 F3 是一个 α 螺旋，它结合在 SH2 结构域的另一侧与磷酸肽结合位点。 F3：外部位点结合似乎可以稳定 SOCS2-SH2 结构域，导致磷酸化配体解离速度减慢，从而增强结合亲和力。 SH2:pTyr 结合亲和力的这种生物物理增强转化为增加 SOCS2 对 GH 信号传导的抑制。