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首页> 外文期刊>Biochemistry >Two Loops Undergoing Concerted Dynamics Regulate the Activity of the ASH1L Histone Methyltransferase
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Two Loops Undergoing Concerted Dynamics Regulate the Activity of the ASH1L Histone Methyltransferase

机译：正在进行协调动力学的两个回路调节ASH1L组蛋白甲基转移酶的活性

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摘要

ASH1L (absent, small, or homeotic-like 1) is a histone methyltransferase (HMTase) involved in gene activation that is overexpressed in multiple forms of cancer. Previous studies of ASH1L's catalytic SET domain identified an autoinhibitory loop that blocks access of histone substrate to the enzyme active site. Here, we used both nuclear magnetic resonance and X-ray crystallography to identify conformational dynamics in the ASH1L autoinhibitory loop. Using site-directed mutagenesis, we found that point mutations in the autoinhibitory loop that perturb the structure of the SET domain result in decreased enzyme activity, indicating that the autoinhibitory loop is not a simple gate to the active site but is rather a key feature critical to ASH1L function. We also identified a second loop in the SET-I subdomain of ASH1L that experiences conformational dynamics, and we trapped two different conformations of this loop using crystallographic studies. Mutation of the SET-I loop led to a large decrease in ASH1L enzymatic activity in addition to a significant conformational change in the SET-I loop, demonstrating the importance of the structure and dynamics of the SET-I loop to ASH1L function. Furthermore, we found that three C-terminal chromatin-interacting domains greatly enhance ASH1L enzymatic activity and that ASH1L requires native nucleosome substrate for robust activity. Our study illuminates the role of concerted conformational dynamics in ASH1L function and identifies structural features important for ASH1L enzymatic activity.
机译：ASH1L（缺失，很小或类似同源的1）是一种组蛋白甲基转移酶（HMTase），参与基因激活，在多种形式的癌症中均过表达。以前对ASH1L的催化SET结构域的研究确定了一个自动抑制环，该环阻止了组蛋白底物进入酶活性位点。在这里，我们使用核磁共振和X射线晶体学来确定ASH1L自抑制环中的构象动力学。使用定点诱变，我们发现扰动SET域结构的自抑制环中的点突变会导致酶活性降低，这表明自抑制环不是通往活性位点的简单门，而是关键的关键特征到ASH1L功能。我们还确定了ASH1L的SET-1子域中的第二个环，该环经历构象动力学，并使用晶体学研究捕获了该环的两个不同构象。 SET-I环的突变除了在SET-I环中显着的构象变化之外，还导致ASH1L酶活性的大幅降​​低，这表明SET-I环的结构和动力学对ASH1L功能的重要性。此外，我们发现三个C端染色质相互作用域大大增强了ASH1L的酶促活性，而ASH1L需要天然核小体底物才能具有强大的活性。我们的研究阐明了协同构象动力学在ASH1L功能中的作用，并确定了对ASH1L酶活性重要的结构特征。

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