Structural basis of SIRT7 nucleosome engagement and substrate specificity
Abstract Chromatin-modifying enzymes target distinct residues within histones to finetune gene expression profiles. SIRT7 is an NAD+-dependent deacylase often deregulated in cancer, which deacetylates either H3 lysine 36 (H3K36) or H3K18 with high specificity within nucleosomes. Here, we report stru...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56529-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861855553060864 |
|---|---|
| author | Carlos Moreno-Yruela Babatunde E. Ekundayo Polina N. Foteva Dongchun Ni Esther Calvino-Sanles Henning Stahlberg Beat Fierz |
| author_facet | Carlos Moreno-Yruela Babatunde E. Ekundayo Polina N. Foteva Dongchun Ni Esther Calvino-Sanles Henning Stahlberg Beat Fierz |
| author_sort | Carlos Moreno-Yruela |
| collection | DOAJ |
| description | Abstract Chromatin-modifying enzymes target distinct residues within histones to finetune gene expression profiles. SIRT7 is an NAD+-dependent deacylase often deregulated in cancer, which deacetylates either H3 lysine 36 (H3K36) or H3K18 with high specificity within nucleosomes. Here, we report structures of nucleosome-bound SIRT7, and uncover the structural basis of its specificity towards H3K36 and K18 deacylation, combining a mechanism-based cross-linking strategy, cryo-EM, and enzymatic and cellular assays. We show that the SIRT7 N-terminus represents a unique, extended nucleosome-binding domain, reaching across the nucleosomal surface to the acidic patch. The catalytic domain binds at the H3-tail exit site, engaging both DNA gyres of the nucleosome. Contacting H3K36 versus H3K18 requires a change in binding pose, and results in structural changes in both SIRT7 and the nucleosome. These structures reveal the basis of lysine specificity, allowing us to engineer SIRT7 towards enhanced H3K18ac selectivity, and provides a basis for small molecule modulator development. |
| format | Article |
| id | doaj-art-f1deeeda25af4cfdac10d77aaef16a80 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f1deeeda25af4cfdac10d77aaef16a802025-02-09T12:44:24ZengNature PortfolioNature Communications2041-17232025-02-0116111510.1038/s41467-025-56529-yStructural basis of SIRT7 nucleosome engagement and substrate specificityCarlos Moreno-Yruela0Babatunde E. Ekundayo1Polina N. Foteva2Dongchun Ni3Esther Calvino-Sanles4Henning Stahlberg5Beat Fierz6Laboratory of Biophysical Chemistry of Macromolecules (LCBM), Institute of Chemical Sciences and Engineering (ISIC), School of Basic Sciences (SB), EPFLLaboratory of Biological Electron Microscopy (LBEM), Institute of Physics (IPHYS), School of Basic Sciences (SB), EPFLLaboratory of Biophysical Chemistry of Macromolecules (LCBM), Institute of Chemical Sciences and Engineering (ISIC), School of Basic Sciences (SB), EPFLLaboratory of Biological Electron Microscopy (LBEM), Institute of Physics (IPHYS), School of Basic Sciences (SB), EPFLLaboratory of Biophysical Chemistry of Macromolecules (LCBM), Institute of Chemical Sciences and Engineering (ISIC), School of Basic Sciences (SB), EPFLLaboratory of Biological Electron Microscopy (LBEM), Institute of Physics (IPHYS), School of Basic Sciences (SB), EPFLLaboratory of Biophysical Chemistry of Macromolecules (LCBM), Institute of Chemical Sciences and Engineering (ISIC), School of Basic Sciences (SB), EPFLAbstract Chromatin-modifying enzymes target distinct residues within histones to finetune gene expression profiles. SIRT7 is an NAD+-dependent deacylase often deregulated in cancer, which deacetylates either H3 lysine 36 (H3K36) or H3K18 with high specificity within nucleosomes. Here, we report structures of nucleosome-bound SIRT7, and uncover the structural basis of its specificity towards H3K36 and K18 deacylation, combining a mechanism-based cross-linking strategy, cryo-EM, and enzymatic and cellular assays. We show that the SIRT7 N-terminus represents a unique, extended nucleosome-binding domain, reaching across the nucleosomal surface to the acidic patch. The catalytic domain binds at the H3-tail exit site, engaging both DNA gyres of the nucleosome. Contacting H3K36 versus H3K18 requires a change in binding pose, and results in structural changes in both SIRT7 and the nucleosome. These structures reveal the basis of lysine specificity, allowing us to engineer SIRT7 towards enhanced H3K18ac selectivity, and provides a basis for small molecule modulator development.https://doi.org/10.1038/s41467-025-56529-y |
| spellingShingle | Carlos Moreno-Yruela Babatunde E. Ekundayo Polina N. Foteva Dongchun Ni Esther Calvino-Sanles Henning Stahlberg Beat Fierz Structural basis of SIRT7 nucleosome engagement and substrate specificity Nature Communications |
| title | Structural basis of SIRT7 nucleosome engagement and substrate specificity |
| title_full | Structural basis of SIRT7 nucleosome engagement and substrate specificity |
| title_fullStr | Structural basis of SIRT7 nucleosome engagement and substrate specificity |
| title_full_unstemmed | Structural basis of SIRT7 nucleosome engagement and substrate specificity |
| title_short | Structural basis of SIRT7 nucleosome engagement and substrate specificity |
| title_sort | structural basis of sirt7 nucleosome engagement and substrate specificity |
| url | https://doi.org/10.1038/s41467-025-56529-y |
| work_keys_str_mv | AT carlosmorenoyruela structuralbasisofsirt7nucleosomeengagementandsubstratespecificity AT babatundeeekundayo structuralbasisofsirt7nucleosomeengagementandsubstratespecificity AT polinanfoteva structuralbasisofsirt7nucleosomeengagementandsubstratespecificity AT dongchunni structuralbasisofsirt7nucleosomeengagementandsubstratespecificity AT esthercalvinosanles structuralbasisofsirt7nucleosomeengagementandsubstratespecificity AT henningstahlberg structuralbasisofsirt7nucleosomeengagementandsubstratespecificity AT beatfierz structuralbasisofsirt7nucleosomeengagementandsubstratespecificity |