Binding to nucleosome poises human SIRT6 for histone H3 deacetylation
Sirtuin 6 (SIRT6) is an NAD+-dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic homeostasis and lifespan. Unlike other sirtuins, it has low affinity to free histone tails but demonstr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/87989 |
| _version_ | 1827339331452272640 |
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| author | Ekaterina Smirnova Emmanuelle Bignon Patrick Schultz Gabor Papai Adam Ben Shem |
| author_facet | Ekaterina Smirnova Emmanuelle Bignon Patrick Schultz Gabor Papai Adam Ben Shem |
| author_sort | Ekaterina Smirnova |
| collection | DOAJ |
| description | Sirtuin 6 (SIRT6) is an NAD+-dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic homeostasis and lifespan. Unlike other sirtuins, it has low affinity to free histone tails but demonstrates strong binding to nucleosomes. It is poorly understood how SIRT6 docking on nucleosomes stimulates its histone deacetylation activity. Here, we present the structure of human SIRT6 bound to a nucleosome determined by cryogenic electron microscopy. The zinc finger domain of SIRT6 associates tightly with the acidic patch of the nucleosome through multiple arginine anchors. The Rossmann fold domain binds to the terminus of the looser DNA half of the nucleosome, detaching two turns of the DNA from the histone octamer and placing the NAD+ binding pocket close to the DNA exit site. This domain shows flexibility with respect to the fixed zinc finger and moves with, but also relative to, the unwrapped DNA terminus. We apply molecular dynamics simulations of the histone tails in the nucleosome to show that in this mode of interaction, the active site of SIRT6 is perfectly poised to catalyze deacetylation of the H3 histone tail and that the partial unwrapping of the DNA allows even lysines close to the H3 core to reach the enzyme. |
| first_indexed | 2024-03-07T19:57:47Z |
| format | Article |
| id | doaj.art-1e6b6b06a7b744acbbeadc0ce34b2a17 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-07T19:57:47Z |
| publishDate | 2024-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1e6b6b06a7b744acbbeadc0ce34b2a172024-02-28T13:22:40ZengeLife Sciences Publications LtdeLife2050-084X2024-02-011210.7554/eLife.87989Binding to nucleosome poises human SIRT6 for histone H3 deacetylationEkaterina Smirnova0Emmanuelle Bignon1https://orcid.org/0000-0001-9475-5049Patrick Schultz2https://orcid.org/0000-0002-7310-6186Gabor Papai3https://orcid.org/0000-0002-2779-8679Adam Ben Shem4Department of Integrated Structural Biology, IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Université de Strasbourg, IGBMC UMR 7104-UMR-S 1258, Illkirch, France; CNRS, UMR 7104, Illkirch, France; Inserm, UMR-S 1258, Illkirch, FranceUniversité de Lorraine and CNRS, UMR 7019 LPCT, Nancy, FranceDepartment of Integrated Structural Biology, IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Université de Strasbourg, IGBMC UMR 7104-UMR-S 1258, Illkirch, France; CNRS, UMR 7104, Illkirch, France; Inserm, UMR-S 1258, Illkirch, FranceDepartment of Integrated Structural Biology, IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Université de Strasbourg, IGBMC UMR 7104-UMR-S 1258, Illkirch, France; CNRS, UMR 7104, Illkirch, France; Inserm, UMR-S 1258, Illkirch, FranceDepartment of Integrated Structural Biology, IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Université de Strasbourg, IGBMC UMR 7104-UMR-S 1258, Illkirch, France; CNRS, UMR 7104, Illkirch, France; Inserm, UMR-S 1258, Illkirch, FranceSirtuin 6 (SIRT6) is an NAD+-dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic homeostasis and lifespan. Unlike other sirtuins, it has low affinity to free histone tails but demonstrates strong binding to nucleosomes. It is poorly understood how SIRT6 docking on nucleosomes stimulates its histone deacetylation activity. Here, we present the structure of human SIRT6 bound to a nucleosome determined by cryogenic electron microscopy. The zinc finger domain of SIRT6 associates tightly with the acidic patch of the nucleosome through multiple arginine anchors. The Rossmann fold domain binds to the terminus of the looser DNA half of the nucleosome, detaching two turns of the DNA from the histone octamer and placing the NAD+ binding pocket close to the DNA exit site. This domain shows flexibility with respect to the fixed zinc finger and moves with, but also relative to, the unwrapped DNA terminus. We apply molecular dynamics simulations of the histone tails in the nucleosome to show that in this mode of interaction, the active site of SIRT6 is perfectly poised to catalyze deacetylation of the H3 histone tail and that the partial unwrapping of the DNA allows even lysines close to the H3 core to reach the enzyme.https://elifesciences.org/articles/87989sirtuinshistone deacetylationSIRT6HDAC |
| spellingShingle | Ekaterina Smirnova Emmanuelle Bignon Patrick Schultz Gabor Papai Adam Ben Shem Binding to nucleosome poises human SIRT6 for histone H3 deacetylation eLife sirtuins histone deacetylation SIRT6 HDAC |
| title | Binding to nucleosome poises human SIRT6 for histone H3 deacetylation |
| title_full | Binding to nucleosome poises human SIRT6 for histone H3 deacetylation |
| title_fullStr | Binding to nucleosome poises human SIRT6 for histone H3 deacetylation |
| title_full_unstemmed | Binding to nucleosome poises human SIRT6 for histone H3 deacetylation |
| title_short | Binding to nucleosome poises human SIRT6 for histone H3 deacetylation |
| title_sort | binding to nucleosome poises human sirt6 for histone h3 deacetylation |
| topic | sirtuins histone deacetylation SIRT6 HDAC |
| url | https://elifesciences.org/articles/87989 |
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