The structure of the core NuRD repression complex provides insights into its interaction with chromatin.
The structure of the core NuRD repression complex provides insights into its interaction with chromatin.
复制标题
核心NURD抑制复合物的结构为其与染色质相互作用提供了见解。
DOI：
10.7554/elife.13941
复制
发表时间：
2016-04-21
期刊：
影响因子：
7.7
通讯作者：
Schwabe JW
中科院分区：
文献类型：
--
作者：
Millard CJ;Varma N;Saleh A;Morris K;Watson PJ;Bottrill AR;Fairall L;Smith CJ;Schwabe JW
NuRD复合体是一种多蛋白转录辅抑制因子，将组蛋白去乙酰化酶和atp依赖性染色质重塑活性偶联。该复合物调控染色质的高阶结构，在调控基因表达、DNA损伤修复和细胞分化等方面具有重要作用。hdac 1和hdac 2被MTA1共抑制因子募集，形成该复合物的催化核心。组蛋白伴侣蛋白RBBP4，先前已被证明与MTA1的羧基末端尾部结合。我们发现MTA1招募RBBP4的第二个拷贝。晶体结构显示MTA1和RBBP4之间存在广泛的界面。由SAXS和交联支持的EM结构揭示了形成NuRD复合物核心的二聚体HDAC1:MTA1:RBBP4组装的结构。我们发现有证据表明，在这个复合体中，RBBP4介导与组蛋白H3尾部的相互作用，而不是与组蛋白H4的相互作用，这表明NuRD复合体向染色质募集的机制。正确调节我们的基因对生命至关重要。基因是通过作为分子机器的蛋白质组合的作用而主动开启或关闭的。其中一些机器改变了DNA在细胞内的包装方式。包装好的DNA被称为染色质，由DNA包裹在组蛋白周围组成，组蛋白一起形成核小体。改变核小体排列的紧密程度可以改变基因是否活跃：更紧密的排列使得接近DNA片段中的基因变得更加困难，从而使它们失活。在人类中，一种叫做NuRD复合物的蛋白质组合通过从核小体中去除乙酰基使染色质更加紧密。这种复合体对早期发育、基因的稳定和修复都很重要。三种蛋白质组成了它的核心：HDAC1，它从核小体中去除乙酰基；MTA1，作为支架将复合体固定在一起；以及RBBP4，后者能使复合物与核小体相互作用。了解蛋白质复合物是如何组装的可以告诉我们很多关于它们是如何工作的。因此，Millard等人使用了许多结构技术来研究NuRD复合体中三个核心蛋白的三维结构。由此产生的结构揭示了HDAC1、MTA1和RBBP4蛋白如何相互作用，影响复合物如何被招募到核小体中。下一步将是组装NuRD复合体的所有剩余蛋白质，以了解其整体结构。DOI: http://dx.doi.org/10.7554/eLife.13941.002
The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities. The complex regulates the higher-order structure of chromatin, and has important roles in the regulation of gene expression, DNA damage repair and cell differentiation. HDACs 1 and 2 are recruited by the MTA1 corepressor to form the catalytic core of the complex. The histone chaperone protein RBBP4, has previously been shown to bind to the carboxy-terminal tail of MTA1. We show that MTA1 recruits a second copy of RBBP4. The crystal structure reveals an extensive interface between MTA1 and RBBP4. An EM structure, supported by SAXS and crosslinking, reveals the architecture of the dimeric HDAC1:MTA1:RBBP4 assembly which forms the core of the NuRD complex. We find evidence that in this complex RBBP4 mediates interaction with histone H3 tails, but not histone H4, suggesting a mechanism for recruitment of the NuRD complex to chromatin. DOI: http://dx.doi.org/10.7554/eLife.13941.001 The correct regulation of our genes is essential for life. Genes are actively switched on or off through the action of assemblies of proteins that act together as molecular machines. Some of these machines alter the way that DNA is packaged inside cells. Packaged DNA – called chromatin – consists of DNA wrapped around proteins called histones, which together form structures called nucleosomes. Changing how tightly nucleosomes are packed together can alter whether a gene is active: tighter packing makes it harder to access the genes in that stretch of DNA and therefore inactivates them. In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. Understanding how protein complexes are assembled tells us a lot about how they work. Millard et al. have therefore used a number of structural techniques to investigate the three-dimensional architecture of the three core proteins in the NuRD complex. The resulting structures have revealed how the HDAC1, MTA1 and RBBP4 proteins interact to influence how the complex is recruited to nucleosomes. The next step will be to assemble all the remaining proteins of the NuRD complex to understand its architecture as a whole. DOI: http://dx.doi.org/10.7554/eLife.13941.002