Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Berlin, Germany.
Nat Struct Mol Biol. 2012 Aug;19(8):819-23. doi: 10.1038/nsmb.2310. Epub 2012 Jul 15.
Phosphorylation of Ser10 of histone H3 regulates chromosome condensation and transcriptional activity. Using time-resolved, high-resolution NMR spectroscopy, we demonstrate that histone H3 Ser10 phosphorylation inhibits checkpoint kinase 1 (Chk1)- and protein kinase C (PKC)-mediated modification of Thr11 and Thr6, the respective primary substrate sites of these kinases. On unmodified H3, both enzymes also target Ser10 and thereby establish autoinhibitory feedback states on individual H3 tails. Whereas phosphorylated Ser10 does not affect acetylation of Lys14 by Gcn5, phosphorylated Thr11 impedes acetylation. Our observations reveal mechanistic hierarchies of H3 phosphorylation and acetylation events and provide a framework for intramolecular modification cross-talk within the N terminus of histone H3.
组蛋白 H3 的丝氨酸 10 位磷酸化调节染色体凝聚和转录活性。使用时间分辨、高分辨率 NMR 光谱技术，我们证明了组蛋白 H3 丝氨酸 10 位磷酸化抑制了检查点激酶 1（Chk1）和蛋白激酶 C（PKC）介导的 Thr11 和 Thr6 的修饰，这是这两种激酶的主要底物位点。在未修饰的 H3 上，这两种酶还靶向 Ser10，从而在单个 H3 尾部上建立自动抑制反馈状态。虽然磷酸化的 Ser10 不影响 Gcn5 对 Lys14 的乙酰化，但磷酸化的 Thr11 会阻碍乙酰化。我们的观察结果揭示了 H3 磷酸化和乙酰化事件的机制层次结构，并为组蛋白 H3 N 端的分子内修饰交叉对话提供了框架。
