Evolutionarily Conserved Allosteric Communication in Protein Tyrosine Phosphatases
Evolutionarily Conserved Allosteric Communication in Protein Tyrosine Phosphatases
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DOI：
10.1021/acs.biochem.8b00656
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发表时间：
2018-11-13
期刊：
影响因子：
2.9
通讯作者：
Fox, Jerome M.
中科院分区：
文献类型：
--
作者：
Hjortness, Michael K.;Riccardi, Laura;Fox, Jerome M.
蛋白酪氨酸磷酸酶（Protein tyrosine phosphatases，PTPs）是一类重要的调节酶，在多种疾病中表现出异常的活性。因此，这些酶中变构通讯的详细图谱可以揭示生理学相关--也许还有治疗信息--扰动的结构基础（即，突变、翻译后修饰或结合事件）影响它们的催化状态。本研究结合了蛋白酪氨酸磷酸酶1B（PTP 1B）的详细生物物理研究与PTP家族的生物信息学分析，以研究这类酶的变构通信。X射线晶体学、分子动力学模拟和基于序列的统计分析结果表明，PTP 1B具有广泛分布的变构网络，该网络在PTP家族中是进化保守的，动力学研究和突变分析的结果表明，该网络在序列多样的PTP中功能完整。这项研究中解决的变构网络揭示了靶向PTP变构抑制剂的新位点，并有助于解释各种疾病相关突变的功能影响。
Protein tyrosine phosphatases (PTPs) are an important class of regulatory enzymes that exhibit aberrant activities in a wide range of diseases. A detailed mapping of allosteric communication in these enzymes could, thus, reveal the structural basis of physiologically relevant-and, perhaps, therapeutically informative-perturbations (i.e., mutations, post-translational modifications, or binding events) that influence their catalytic states. This study combines detailed biophysical studies of protein tyrosine phosphatase 1B (PTP1B) with bioinformatic analyses of the PTP family to examine allosteric communication in this class of enzymes. Results of X-ray crystallography, molecular dynamics simulations, and sequence-based statistical analyses indicate that PTP1B possesses a broadly distributed allosteric network that is evolutionarily conserved across the PTP family, and findings from both kinetic studies and mutational analyses show that this network is functionally intact in sequence-diverse PTPs. The allosteric network resolved in this study reveals new sites for targeting allosteric inhibitors of PTPs and helps explain the functional influence of a diverse set of disease-associated mutations.