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组蛋白 H4 赖氨酸 20 位的 SET8 甲基转移酶介导的核小体结构基础。

Structural basis of nucleosomal histone H4 lysine 20 methylation by SET8 methyltransferase.

机构信息

Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.

Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.

出版信息

Life Sci Alliance. 2021 Feb 11;4(4). doi: 10.26508/lsa.202000919. Print 2021 Apr.

DOI:10.26508/lsa.202000919
PMID:33574035
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7893823/
Abstract

SET8 is solely responsible for histone H4 lysine-20 (H4K20) monomethylation, which preferentially occurs in nucleosomal H4. However, the underlying mechanism by which SET8 specifically promotes the H4K20 monomethylation in the nucleosome has not been elucidated. Here, we report the cryo-EM structures of the human SET8-nucleosome complexes with histone H3 and the centromeric H3 variant, CENP-A. Surprisingly, we found that the overall cryo-EM structures of the SET8-nucleosome complexes are substantially different from the previous crystal structure models. In the complexes with H3 and CENP-A nucleosomes, SET8 specifically binds the nucleosomal acidic patch via an arginine anchor, composed of the Arg188 and Arg192 residues. Mutational analyses revealed that the interaction between the SET8 arginine anchor and the nucleosomal acidic patch plays an essential role in the H4K20 monomethylation activity. These results provide the groundwork for understanding the mechanism by which SET8 specifically accomplishes the H4K20 monomethylation in the nucleosome.

摘要

SET8 全权负责组蛋白 H4 赖氨酸 20（H4K20）单甲基化，该过程优先发生在核小体 H4 中。然而，SET8 特异性促进核小体中 H4K20 单甲基化的潜在机制尚未阐明。在此，我们报告了人 SET8-核小体复合物与组蛋白 H3 和着丝粒 H3 变体 CENP-A 的冷冻电镜结构。令人惊讶的是，我们发现 SET8-核小体复合物的整体冷冻电镜结构与之前的晶体结构模型有很大的不同。在含有 H3 和 CENP-A 核小体的复合物中，SET8 通过由 Arg188 和 Arg192 残基组成的精氨酸锚定点特异性地结合核小体酸性斑。突变分析表明，SET8 精氨酸锚定点与核小体酸性斑之间的相互作用在 H4K20 单甲基化活性中起着至关重要的作用。这些结果为理解 SET8 在核小体中特异性完成 H4K20 单甲基化的机制提供了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/924942bd9044/LSA-2020-00919_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/84398d8192f7/LSA-2020-00919_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/4955a9501193/LSA-2020-00919_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/6e188c9afc3c/LSA-2020-00919_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/f8e644053af0/LSA-2020-00919_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/5ae204255db0/LSA-2020-00919_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/b8a8dc623baf/LSA-2020-00919_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/5d8acc6fe218/LSA-2020-00919_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/0fa77d99e457/LSA-2020-00919_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/e85f874d4efc/LSA-2020-00919_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/2b538af51019/LSA-2020-00919_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/924942bd9044/LSA-2020-00919_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/84398d8192f7/LSA-2020-00919_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/4955a9501193/LSA-2020-00919_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/6e188c9afc3c/LSA-2020-00919_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/f8e644053af0/LSA-2020-00919_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/5ae204255db0/LSA-2020-00919_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/b8a8dc623baf/LSA-2020-00919_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/5d8acc6fe218/LSA-2020-00919_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/0fa77d99e457/LSA-2020-00919_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/e85f874d4efc/LSA-2020-00919_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/2b538af51019/LSA-2020-00919_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7688/7893823/924942bd9044/LSA-2020-00919_Fig4.jpg

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