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首页> 外文期刊>Journal of Molecular Biology >CENP-A Nucleosome is a Sensitive Allosteric Scaffold for DNA and Chromatin Factors
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CENP-A Nucleosome is a Sensitive Allosteric Scaffold for DNA and Chromatin Factors

机译：CENP-A核小体是用于DNA和染色质因子的敏感的变形支架

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Centromeric loci of chromosomes are defined by nucleosomes containing the histone H3 variant CENP-A, which bind their DNA termini more permissively than their canonical counterpart, a feature that is critical for the mitotic fidelity. A recent cryo-EM study demonstrated that the DNA termini of CENP-A nucleosomes, reconstituted with the Widom 601 DNA sequence, are asymmetrically flexible, meaning one terminus is more clearly resolved than the other. However, an earlier work claimed that both ends could be resolved in the presence of two stabilizing single chain variable fragment (scFv) antibodies per nucleosome, and thus are likely permanently bound to the histone octamer. This suggests that the binding of scFv antibodies to the histone octamer surface would be associated with CENP-A nucleosome conformational changes, including stable binding of the DNA termini. Here, we present computational evidence that allows to explain at atomistic level the structural rearrangements of CENP-A nucleosomes resulting from the antibody binding. The antibodies, while they only bind the octamer facades are capable of altering the dynamics of the nucleosomal core, and indirectly also the surrounding DNA. This effect has more drastic implications for the structure and the dynamics of the CENP-A nucleosome in comparison to its canonical counterpart. Furthermore, we find evidence that the antibodies bind the left and the right octamer facades at different affinities, another manifestation of the DNA sequence. We speculate that the cells could use induction of similar allosteric effects to control centromere function. (C) 2020 Elsevier Ltd. All rights reserved.
机译：染色体的着丝粒位点是由含有组蛋白H3变体CENP-A的核小体定义的，它比其典型对应物更容易结合其DNA末端，这一特征对有丝分裂保真度至关重要。最近的一项冷冻电镜研究表明，用Widom 601 DNA序列重组的CENP-A核小体的DNA末端具有不对称的灵活性，这意味着一个末端比另一个末端更清晰。然而，一项早期的研究声称，在每个核小体中存在两个稳定的单链可变片段（scFv）抗体的情况下，两端都可以分解，因此可能永久性地结合到组蛋白八聚体上。这表明单链抗体与组蛋白八聚体表面的结合与CENP-A核小体构象变化有关，包括DNA末端的稳定结合。在这里，我们提供了计算证据，可以在原子水平上解释抗体结合导致的CENP-A核小体的结构重排。这些抗体虽然只结合八聚体表面，但它们能够改变核小体核心的动态，并间接改变周围的DNA。与经典的CENP-A核小体相比，这种效应对CENP-A核小体的结构和动力学有更为重大的影响。此外，我们发现证据表明抗体以不同的亲和力结合左右八聚体表面，这是DNA序列的另一种表现。我们推测这些细胞可以通过诱导类似的变构效应来控制着丝粒功能。（C） 2020爱思唯尔有限公司版权所有。

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