Michael addition of dehydroalanine-containing MAPK peptides to catalytic lysine inhibits the activity of phosphothreonine lyase
Michael addition of dehydroalanine-containing MAPK peptides to catalytic lysine inhibits the activity of phosphothreonine lyase
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Michael 将含脱氢丙氨酸的 MAPK 肽添加到催化赖氨酸中抑制磷酸苏氨酸裂解酶的活性
DOI：
10.1016/j.febslet.2015.10.025
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发表时间：
2015-11-30
期刊：
影响因子：
3.5
通讯作者：
Li，Hongtao
中科院分区：
文献类型：
--
作者：
Zhang，Yuan;Yang，Ru;Li，Hongtao
磷酸苏氨酸裂解酶OspF和SpvC通过β-消除不可逆地破坏宿主双磷酸化的促分裂原活化蛋白激酶（MAPK）[pThr-X-pTyr基序]。我们发现，双磷酸化（pSer-X-pTyr）MAPK底物肽和它们产生的催化产物交联OspF和SpvC。质谱分析结果显示，这些连接形成之间的赖氨酸，它作为一个通用的基地，和脱氢丙氨酸（Dha）的催化产物。亲核加成效率取决于K136残基处于去质子化状态。肽交联抑制SpvC的活性并阻断SpvC对MAPK信号传导的失活。模拟这些序列的小分子化合物可以作为磷酸苏氨酸裂解酶抑制剂。
The phosphothreonine lyases OspF and SpvC irreversibly inactivate host dual-phosphorylated mitogen-activated protein kinases (MAPKs) [pThr-X-pTyr motif] through β-elimination. We found that dual-phosphorylated (pSer-X-pTyr) MAPK substrate peptides and their resulting catalytic products cross-link to OspF and SpvC. Mass spectrometry results revealed that these linkages form between lysine, which acts as a general base, and dehydroalanine (Dha) on catalytic products. The nucleophilic addition efficiency is dependent on the K136 residue being in a deprotonated state. Peptide cross-linking inhibits the activity of SpvC and blocks the inactivation of MAPK signaling by SpvC. Small compounds mimicking these sequences may act as phosphothreonine lyase inhibitors.