Diversity in peptide recognition by the SH2 domain of SH2B1
Diversity in peptide recognition by the SH2 domain of SH2B1
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DOI：
10.1002/prot.25420
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发表时间：
2018-02-01
影响因子：
2.9
通讯作者：
Wuttke, Deborah S.
中科院分区：
文献类型：
--
作者：
McKercher, Marissa A.;Guan, Xiaoyang;Wuttke, Deborah S.
SH2B1是一种多域蛋白，是调节胰岛素、瘦素和生长激素信号通路等多种细胞事件的关键适配子。许多蛋白质-蛋白质相互作用是由SH2B1的SH2结构域介导的，该结构域识别含有磷酸化酪氨酸(Py)的配体，包括来自Janus Kinase 2、胰岛素受体和胰岛素受体底物-1和-2的多肽。SH2B1的SH2结构域的特异性在这些配体中是由Py的+3位C末端的疏水或酸性侧链赋予的。这种化学上不同物种的特异性表明SH2B1依赖于不同的热力学或结构机制来与多肽结合。使用结合和结构策略，我们已经确定了每种肽结合模式的独特热力学特征，以及几个在肽结合中发挥不同作用的SH2B1残基，包括K575和R578。SH2B1的SH2结构域的高分辨率结构进一步揭示了构象可塑性蛋白质环，这可能有助于蛋白质识别不同的配体。总之，除了骨架构象的灵活性外，大量的疏水和静电相互作用允许SH2B1识别不同的多肽。对这种扩展的肽识别的理解将有助于识别新的生理相关的SH2B1/肽相互作用，这将有助于肥胖症和糖尿病药物的设计，以高特异性地靶向SH2B1的配体结合界面。
SH2B1 is a multidomain protein that serves as a key adaptor to regulate numerous cellular events, such as insulin, leptin, and growth hormone signaling pathways. Many of these protein-protein interactions are mediated by the SH2 domain of SH2B1, which recognizes ligands containing a phosphorylated tyrosine (pY), including peptides derived from janus kinase 2, insulin receptor, and insulin receptor substrate-1 and -2. Specificity for the SH2 domain of SH2B1 is conferred in these ligands either by a hydrophobic or an acidic side chain at the +3 position C-terminal to the pY. This specificity for chemically disparate species suggests that SH2B1 relies on distinct thermodynamic or structural mechanisms to bind to peptides. Using binding and structural strategies, we have identified unique thermodynamic signatures for each peptide binding mode, and several SH2B1 residues, including K575 and R578, that play distinct roles in peptide binding. The high-resolution structure of the SH2 domain of SH2B1 further reveals conformationally plastic protein loops that may contribute to the ability of the protein to recognize dissimilar ligands. Together, numerous hydrophobic and electrostatic interactions, in addition to backbone conformational flexibility, permit the recognition of diverse peptides by SH2B1. An understanding of this expanded peptide recognition will allow for the identification of novel physiologically relevant SH2B1/peptide interactions, which can contribute to the design of obesity and diabetes pharmaceuticals to target the ligand-binding interface of SH2B1 with high specificity.