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Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2
https://repo.qst.go.jp/records/84560
https://repo.qst.go.jp/records/84560c2455f7f-dc63-462c-a6ed-bedb9a57304c
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2020-12-03 | |||||
| タイトル | ||||||
| タイトル | Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2 | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Sato, Ko
× Sato, Ko× Kumar, Amarjeet× Hamada, Keisuke× Okada, Chikako× Oguni, Asako× Machida, Ayumu× Sakuraba, Shun× Nishizawa, Tomohiro× Nureki, Osamu× Kono, Hidetoshi× Ogata, Kazuhiro× Sengoku, Toru× Kumar, Amarjeet× Shun, Sakuraba× Hidetoshi, Kono |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide the development of specific inhibitors of NSD2. | |||||
| 書誌情報 |
nature communications 巻 12, 号 1, p. 6605, 発行日 2021-11 |
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| 出版者 | ||||||
| 出版者 | Nature | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 2041-1723 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1038/s41467-021-26913-5 | |||||
| 関連サイト | ||||||
| 識別子タイプ | URI | |||||
| 関連識別子 | https://www.ncbi.nlm.nih.gov/pubmed/34782608 | |||||
