Distinct structural bases for sequence-specific DNA binding by mammalian BEN domain proteins.
Distinct structural bases for sequence-specific DNA binding by mammalian BEN domain proteins.
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哺乳动物 BEN 结构域蛋白序列特异性 DNA 结合的独特结构基础
DOI：
10.1101/gad.348993.121
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发表时间：
2022-02-01
影响因子：
10.5
通讯作者：
Lai EC
中科院分区：
文献类型：
--
作者：
Zheng L;Liu J;Niu L;Kamran M;Yang AWH;Jolma A;Dai Q;Hughes TR;Patel DJ;Zhang L;Prasanth SG;Yu Y;Ren A;Lai EC
在这项研究中，Zheng等人研究了BEN因子（一种最近被认可的DNA结合模块）如何在人体中识别其靶标。他们描述了几种哺乳动物BEN结构域（BD）因子，包括来自两个NACC家族的BTB-BEN蛋白和来自BEND3的四个BD蛋白，并提供了哺乳动物BEN蛋白序列特异性DNA结合的结构见解。BEN结构域是最近发现的存在于多种后生动物和某些病毒中的DNA结合模块。几个BEN结构域因子被称为转录抑制因子，但是，总的来说，相对而言，人们对BEN因子如何识别它们在人类中的靶标知之甚少。特别是，BEN结构域的x射线结构：DNA复合物仅为携带单个BEN结构域的果蝇因子所知，缺乏直接的脊椎动物同源物。在这里，我们描述了几种哺乳动物BEN结构域（BD）因子，包括来自两个NACC家族BTB-BEN蛋白和来自BEND3的四个BD。体外选择数据显示，从所有这些因素中分离的BEN结构域具有序列特异性结合活性。我们对BEND3进行了详细的功能、基因组和结构研究。我们发现BD4是体内关联和抑制内源性BEND3靶点的主要决定因素。我们获得了BEND3- bd4结合其首选结合位点的高分辨率结构，揭示了BEND3如何识别同源DNA靶标，并显示了与其非DNA结合BEN结构域之一（BD1）的差异。最后，与我们之前的无脊椎动物BEN结构进行比较，以及使用AlphaFold2和RoseTTAFold进行额外的结构预测，揭示了不同类型BEN结构域蛋白对靶DNA识别的不同策略。总之，这些研究扩展了BEN因子的DNA识别活性，并提供了哺乳动物BEN蛋白序列特异性DNA结合的结构见解。
In this study, Zheng et al. investigated how BEN factors, a recently recognized DNA binding module, identify their targets in humans. They characterize several mammalian BEN domain (BD) factors, including from two NACC family BTB-BEN proteins and from BEND3, which has four BDs, and provide structural insights into sequence-specific DNA binding by mammalian BEN proteins. The BEN domain is a recently recognized DNA binding module that is present in diverse metazoans and certain viruses. Several BEN domain factors are known as transcriptional repressors, but, overall, relatively little is known of how BEN factors identify their targets in humans. In particular, X-ray structures of BEN domain:DNA complexes are only known for Drosophila factors bearing a single BEN domain, which lack direct vertebrate orthologs. Here, we characterize several mammalian BEN domain (BD) factors, including from two NACC family BTB-BEN proteins and from BEND3, which has four BDs. In vitro selection data revealed sequence-specific binding activities of isolated BEN domains from all of these factors. We conducted detailed functional, genomic, and structural studies of BEND3. We show that BD4 is a major determinant for in vivo association and repression of endogenous BEND3 targets. We obtained a high-resolution structure of BEND3-BD4 bound to its preferred binding site, which reveals how BEND3 identifies cognate DNA targets and shows differences with one of its non-DNA-binding BEN domains (BD1). Finally, comparison with our previous invertebrate BEN structures, along with additional structural predictions using AlphaFold2 and RoseTTAFold, reveal distinct strategies for target DNA recognition by different types of BEN domain proteins. Together, these studies expand the DNA recognition activities of BEN factors and provide structural insights into sequence-specific DNA binding by mammalian BEN proteins.
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影响因子：
10.5
作者：
Dai Q;Ren A;Westholm JO;Duan H;Patel DJ;Lai EC
通讯作者：
Lai EC
影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
DOI：
10.1073/pnas.0711961105
发表时间：
2008-04-22
影响因子：
11.1
作者：
Feng, Ru;Desbordes, Sabrina C.;Graf, Thomas
通讯作者：
Graf, Thomas
影响因子：
14.9
作者：
Bailey TL;Johnson J;Grant CE;Noble WS
通讯作者：
Noble WS
影响因子：
3.5
作者：
Aghajanirefah, A.;Nguyen, L. N.;Ohadi, M.
通讯作者：
Ohadi, M.