Crystal Structure and Substrate Specificity of PTPN12
Crystal Structure and Substrate Specificity of PTPN12
复制标题
PTPN12的晶体结构和底物特异性
DOI：
10.1016/j.celrep.2016.04.016
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发表时间：
2016-05-10
期刊：
影响因子：
8.8
通讯作者：
Yu, Xiao
中科院分区：
文献类型：
--
作者：
Li, Hui;Yang, Fan;Yu, Xiao
PTPN12是一种重要的肿瘤抑制因子，在多种生理过程中发挥关键作用。然而，PTPN12的底物特异性的分子基础仍然不确定。在这里，酶学和晶体学研究使我们能够确定两个不同的结构特征，是PTPN 12底物特异性的关键决定因素：pY+1位点结合口袋和特定的碱性带电残基沿着其表面环。PTPN12中的关键结构可塑性区域和特定残基能够识别不同的HER2磷酸化位点并调节特定的PTPN12功能。此外，PTPN12的结构揭示了在特定PTPN12环中的CDK2磷酸化位点。综上所述，我们的研究结果不仅提供了PTPN 12的工作机制，其底物的去磷酸化，但也将有助于设计PTPN 12的特异性抑制剂。
PTPN12 is an important tumor suppressor that plays critical roles in various physiological processes. However, the molecular basis underlying the substrate specificity of PTPN12 remains uncertain. Here, enzymological and crystallographic studies have enabled us to identify two distinct structural features that are crucial determinants of PTPN12 substrate specificity: the pY+1 site binding pocket and specific basic charged residues along its surface loops. Key structurally plastic regions and specific residues in PTPN12 enabled recognition of different HER2 phosphorylation sites and regulated specific PTPN12 functions. In addition, the structure of PTPN12 revealed a CDK2 phosphorylation site in a specific PTPN12 loop. Taken together, our results not only provide the working mechanisms of PTPN12 for desphosphorylation of its substrates but will also help in designing specific inhibitors of PTPN12.