肽开关对于 Sirt1 去乙酰化酶活性是必需的。
Peptide switch is essential for Sirt1 deacetylase activity.
机构信息
Laboratory of Obesity and Aging Research, Genetics and Development Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Mol Cell. 2011 Oct 21;44(2):203-13. doi: 10.1016/j.molcel.2011.07.038.
In mammals, the Sirtuins are composed of seven Sir2 orthologs (Sirt1-7) with a conserved deacetylase core that utilizes NAD(+) as a cofactor. Interestingly, the deacetylase core of Sirt1 by itself has no catalytic activity. We found within the C-terminal domain a 25 aa sequence that is essential for Sirt1 activity (ESA). Our results indicate that the ESA region interacts with and functions as an "on switch" for the deacetylase core. The endogenous Sirt1 inhibitor DBC1, which also binds to the deacetylase core, competes with and inhibits the ESA region from interacting with the deacetylase core. We discovered an ESA mutant peptide that can bind to the deacetylase core and inhibit Sirt1 in trans. By using this mutant peptide, we were able to inhibit Sirt1 activity and to increase the chemosensitivity of androgen-refractory prostate cancer cells. Therefore, the ESA region is a potential target for development of therapies to regulate Sirt1.
在哺乳动物中，Sirtuins 由七个 Sirt2 同源物（Sirt1-7）组成，具有保守的脱乙酰酶核心，利用 NAD(+)作为辅助因子。有趣的是，Sirt1 的脱乙酰酶核心本身没有催化活性。我们在 C 末端结构域中发现了一个 25 个氨基酸的序列，该序列对于 Sirt1 活性（ESA）是必需的。我们的结果表明，ESA 区域与脱乙酰酶核心相互作用，并作为脱乙酰酶核心的“开启开关”发挥作用。内源性 Sirt1 抑制剂 DBC1 也与脱乙酰酶核心结合，与 ESA 区域竞争并抑制其与脱乙酰酶核心的相互作用。我们发现了一种 ESA 突变肽，它可以与脱乙酰酶核心结合并在转染中抑制 Sirt1。通过使用这种突变肽，我们能够抑制 Sirt1 活性并增加雄激素难治性前列腺癌细胞的化疗敏感性。因此，ESA 区域是开发调节 Sirt1 疗法的潜在靶点。
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