Histone deacetylase 3 (HDAC3) plays an important role in signal-dependent transcription and is dysregulated in diseases such as cancer. Previous studies have shown that the function of HDAC3 requires an activation step, which is mediated by the interactions of HDAC3 with the deacetylase-activation domain (DAD) of nuclear receptor corepressors and inositol tetraphosphate (IP4). However, the role of the unique HDAC3 C-terminal region in HDAC3 activation is elusive. Here multiple biochemical, structural, and functional studies show that HDAC3 activation requires a priming step mediated by the C terminus to remodel HDAC3 conformation. We show that multiple C-terminal mutations prevent HDAC3 activation by preventing this C terminus-dependent conformational change. Mechanistically, we demonstrate that the C terminus-mediated function in altering HDAC3 conformation is required for proper complex formation of HDAC3 with DAD and IP4 by allowing HDAC3 to undergo IP4-dependent interaction with DAD. Remarkably, we found that this C terminus function is conformation dependent, being necessary for HDAC3 activation prior to but not after the conformational change. Together, our study defines two functional states of free HDAC3, reveals the complete HDAC3 activation pathway, and links the C terminus function to the specific interaction between HDAC3 and DAD. These results also have implications in how signaling pathways may converge on the C terminus to regulate HDAC3 and suggest that the C terminus-mediated conformational change could represent a new target for inhibiting HDAC3 in diseases such as cancer.

中文翻译：

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核受体辅助抑制因子激活 HDAC3 需要 AC 末端依赖的构象变化。

组蛋白去乙酰化酶 3 (HDAC3) 在信号依赖性转录中起重要作用，并且在癌症等疾病中失调。先前的研究表明，HDAC3 的功能需要一个激活步骤，这是由 HDAC3 与核受体辅助抑制因子的脱乙酰酶激活域 (DAD) 和四磷酸肌醇 (IP4) 的相互作用介导的。然而，独特的 HDAC3 C 端区域在 HDAC3 激活中的作用是难以捉摸的。在这里，多项生化、结构和功能研究表明 HDAC3 激活需要由 C 末端介导的引发步骤来重塑 HDAC3 构象。我们表明多个 C 端突变通过阻止这种 C 端依赖的构象变化来阻止 HDAC3 激活。从机制上讲，我们证明，通过允许 HDAC3 与 DAD 进行依赖于 IP4 的相互作用，C 末端介导的改变 HDAC3 构象的功能是 HDAC3 与 DAD 和 IP4 正确形成复合物所必需的。值得注意的是，我们发现这个 C 末端功能是构象依赖性的，在构象变化之前但不是之后激活 HDAC3 是必需的。总之，我们的研究定义了游离 HDAC3 的两种功能状态，揭示了完整的 HDAC3 激活途径，并将 C 末端功能与 HDAC3 和 DAD 之间的特定相互作用联系起来。这些结果也对信号通路如何在 C 末端汇聚以调节 HDAC3 产生影响，并表明 C 末端介导的构象变化可能代表在癌症等疾病中抑制 HDAC3 的新靶点。