Recognition of Histone H3 Methylation States by the PHD1 Domain of Histone Demethylase KDM5A.
Recognition of Histone H3 Methylation States by the PHD1 Domain of Histone Demethylase KDM5A.
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DOI：
10.1021/acschembio.0c00976
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发表时间：
2023-09-15
影响因子：
4
通讯作者：
Fujimori DG
中科院分区：
文献类型：
--
作者：
Longbotham JE;Kelly MJS;Fujimori DG
PHD阅读器结构域是染色质结合模块，通常负责募集含有组蛋白修饰酶、染色质重塑剂和DNA修复机制的大蛋白质复合物。大多数PHD结构域识别组蛋白H3的N-末端残基，并且对组蛋白H3中的Lys 4（H3 K4）的甲基化状态敏感。组蛋白去甲基化酶KDM 5A是一种含有三个PHD结构域的表观遗传擦除酶，通常在各种癌症中过表达，当其PHD 1结构域与H3尾结合时，其去甲基化活性变构增强。PHD 1的变构调节功能扩展了阅读器结构域的作用，表明这种染色质相互作用模块的独特功能。我们先前的研究确定了PHD 1的H3结合位点，尽管尚不清楚H3尾如何与PHD 1的N-末端残基相互作用以及PHD 1如何区分具有不同程度H3 K4甲基化的H3尾。在这里，我们已经确定了apo和H3结合的PHD 1的溶液结构。我们观察到PHD 1中发生的构象变化，以适应H3，有趣的是，H3以螺旋构象结合。我们还观察到不同的甲基化H3 K4肽（me 0，me 1，me 2，或me 3）的结合残基的差异相互作用，提供了一个理由PHD 1的偏好较低的甲基化状态的H3 K4。我们进一步评估了PHD 1结构域中各种H3相互作用残基对H3肽结合的贡献。H3结合位点的结构细节可以提供有用的信息，以帮助开发KDM 5A的变构小分子调节剂。
PHD reader domains are chromatin binding modules often responsible for the recruitment of large protein complexes that contain histone modifying enzymes, chromatin remodelers, and DNA repair machinery. A majority of PHD domains recognize N-terminal residues of histone H3 and are sensitive to the methylation state of Lys4 in histone H3 (H3K4). Histone demethylase KDM5A, an epigenetic eraser enzyme that contains three PHD domains, is often overexpressed in various cancers, and its demethylation activity is allosterically enhanced when its PHD1 domain is bound to the H3 tail. The allosteric regulatory function of PHD1 expands roles of reader domains, suggesting unique features of this chromatin interacting module. Our previous studies determined the H3 binding site of PHD1, although it remains unclear how the H3 tail interacts with the N-terminal residues of PHD1 and how PHD1 discriminates against H3 tails with varying degrees of H3K4 methylation. Here, we have determined the solution structure of apo and H3 bound PHD1. We observe conformational changes occurring in PHD1 in order to accommodate H3, which interestingly binds in a helical conformation. We also observe differential interactions of binding residues with differently methylated H3K4 peptides (me0, me1, me2, or me3), providing a rationale for PHD1’s preference for lower methylation states of H3K4. We further assessed the contributions of various H3 interacting residues in the PHD1 domain to the binding of H3 peptides. The structural details of the H3 binding site could provide useful information to aid the development of allosteric small molecule modulators of KDM5A.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1042/bcj20161053
发表时间：
2017-05-04
期刊：
The Biochemical journal
影响因子：
--
作者：
Bortoluzzi A;Amato A;Lucas X;Blank M;Ciulli A
通讯作者：
Ciulli A
影响因子：
14.9
作者：
Dreveny I;Deeves SE;Fulton J;Yue B;Messmer M;Bhattacharya A;Collins HM;Heery DM
通讯作者：
Heery DM
影响因子：
50.3
作者：
Hinohara K;Wu HJ;Vigneau S;McDonald TO;Igarashi KJ;Yamamoto KN;Madsen T;Fassl A;Egri SB;Papanastasiou M;Ding L;Peluffo G;Cohen O;Kales SC;Lal-Nag M;Rai G;Maloney DJ;Jadhav A;Simeonov A;Wagle N;Brown M;Meissner A;Sicinski P;Jaffe JD;Jeselsohn R;Gimelbrant AA;Michor F;Polyak K
通讯作者：
Polyak K
影响因子：
8.8
作者：
Klein BJ;Piao L;Xi Y;Rincon-Arano H;Rothbart SB;Peng D;Wen H;Larson C;Zhang X;Zheng X;Cortazar MA;Peña PV;Mangan A;Bentley DL;Strahl BD;Groudine M;Li W;Shi X;Kutateladze TG
通讯作者：
Kutateladze TG