Arif Mohammed, Kumar G V Pavan, Narayana Chandrabhas, Kundu Tapas K
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, and Light Scattering Laboratory, Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P O, Bangalore, India.
J Phys Chem B. 2007 Oct 18;111(41):11877-9. doi: 10.1021/jp0762931. Epub 2007 Sep 26.
Reversible acetylation of histone and non-histone proteins plays an important role in the regulation of gene expression and cellular homeostasis. A balance between acetylation and deacetylation of these proteins are maintained by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among different HATs, p300/CBP is the most widely studied chromatin modifying enzymes. p300 is involved in several physiological processes like cell growth, regulation of gene expression, development, and tumor suppressor, and therefore its dysfunction causes different diseases. The autoacetylation of p300 is one of the key regulators of its catalytic activity. Mechanistically, autoacetylation induced structural changes in the p300 HAT domain acts as a master switch. In this report, we have shown that the natural HAT inhibitor garcinol could potently inhibit the autoacetylation activity. Furthermore, for the first time, we demonstrate that indeed autoacetylation induces structural changes in p300 HAT domain, as probed by surface-enhanced Raman scattering. Presumably, SERS will be a very useful tool to find out the structural changes in the other self-modifying enzymes like kinases and methyltransferases.
组蛋白和非组蛋白的可逆乙酰化在基因表达调控和细胞稳态中发挥着重要作用。这些蛋白质的乙酰化和去乙酰化之间的平衡由组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs）维持。在不同的HATs中，p300/CBP是研究最广泛的染色质修饰酶。p300参与细胞生长、基因表达调控、发育和肿瘤抑制等多种生理过程，因此其功能障碍会导致不同疾病。p300的自身乙酰化是其催化活性的关键调节因子之一。从机制上讲，自身乙酰化诱导p300 HAT结构域的结构变化，起到主控开关的作用。在本报告中，我们表明天然HAT抑制剂藤黄菌素可以有效抑制自身乙酰化活性。此外，我们首次证明，如表面增强拉曼散射所探测的，自身乙酰化确实会诱导p300 HAT结构域的结构变化。据推测，表面增强拉曼散射将是一种非常有用的工具，用于发现其他自我修饰酶（如激酶和甲基转移酶）的结构变化。
