Structural basis of nucleosomal H4K20 recognition and methylation by SUV420H1 methyltransferase.
Structural basis of nucleosomal H4K20 recognition and methylation by SUV420H1 methyltransferase.
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DOI：
10.1038/s41421-023-00620-5
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发表时间：
2023-12-05
期刊：
影响因子：
33.5
通讯作者：
Li, Wanqiu
中科院分区：
文献类型：
--
作者：
Lin, Folan;Zhang, Ruxin;Shao, Weihan;Lei, Cong;Ma, Mingxi;Zhang, Ying;Wen, Zengqi;Li, Wanqiu
组蛋白赖氨酸甲基转移酶SUV 420 H1负责组蛋白H4赖氨酸20（H4 K20）的位点特异性二/三甲基化，在DNA模板化过程中具有关键作用，包括DNA复制、DNA损伤修复和染色质压实。它的突变经常发生在人类癌症中。含有组蛋白变体H2A.Z的核小体增强SUV 420 H1对H4 K20二甲基化沉积的催化活性，调节早期复制起点。然而，SUV 420 H1特异性识别并在核小体上沉积H4 K20甲基标记的分子机制仍然知之甚少。在这里，我们报告的冷冻电镜结构的SUV 420 H1与H2 A的核小体核心颗粒（NCPs），和H2 A。Z的NCPs。我们发现SUV 420 H1与组蛋白和DNA区域进行了广泛的位点特异性接触。SUV 420 H1 C-末端结构域通过其两个精氨酸锚点识别NCP的H2 A-H2 B酸性补丁，从而使H4 K20插入特异性催化。我们还鉴定了增加SUV 420 H1结合至H2A.Z NCP的催化活性的重要残基。在体外和体内功能分析表明，多种疾病相关的突变的接口是必不可少的催化活性和染色质状态调节。总之，我们的研究为SUV 420 H1的基于核小体的识别和甲基化机制提供了分子见解，并为理解SUV 420 H1相关的人类疾病提供了结构基础。
Histone lysine methyltransferase SUV420H1, which is responsible for site-specific di-/tri-methylation of histone H4 lysine 20 (H4K20), has crucial roles in DNA-templated processes, including DNA replication, DNA damage repair, and chromatin compaction. Its mutations frequently occur in human cancers. Nucleosomes containing the histone variant H2A.Z enhance the catalytic activities of SUV420H1 on H4K20 di-methylation deposition, regulating early replication origins. However, the molecular mechanism by which SUV420H1 specifically recognizes and deposits H4K20 methyl marks on nucleosomes remains poorly understood. Here we report the cryo-electron microscopy structures of SUV420H1 associated with H2A-containing nucleosome core particles (NCPs), and H2A.Z-containing NCPs. We find that SUV420H1 makes extensive site-specific contacts with histone and DNA regions. SUV420H1 C-terminal domain recognizes the H2A–H2B acidic patch of NCPs through its two arginine anchors, thus enabling H4K20 insertion for catalysis specifically. We also identify important residues increasing the catalytic activities of SUV420H1 bound to H2A.Z NCPs. In vitro and in vivo functional analyses reveal that multiple disease-associated mutations at the interfaces are essential for its catalytic activity and chromatin state regulation. Together, our study provides molecular insights into the nucleosome-based recognition and methylation mechanisms of SUV420H1, and a structural basis for understanding SUV420H1-related human disease.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
48
作者：
Kastner, Berthold;Fischer, Niels;Stark, Holger
通讯作者：
Stark, Holger
影响因子：
23.9
作者：
Boonsanay, Verawan;Zhang, Ting;Braun, Thomas
通讯作者：
Braun, Thomas
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH