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Updated: May 29, 2025
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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
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Structural basis of SIRT7 nucleosome engagement and substrate specificity
Carlos Moreno-Yruela1, Babatunde E Ekundayo2,3, Polina N Foteva4
1Laboratory of Biophysical Chemistry of Macromolecules (LCBM), Institute of Chemical Sciences and Engineering (ISIC), School of Basic Sciences (SB), EPFL, Lausanne, Switzerland. carlos.morenoyruela@epfl.ch.
Nature Communications
|February 3, 2025
Summary
SIRT7, a cancer-linked enzyme, modifies histones H3K36 and H3K18. Our study reveals its nucleosome binding and specificity, enabling engineered selectivity for therapeutic development.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Chromatin-modifying enzymes regulate gene expression by targeting histone residues.
- Sirtuin 7 (SIRT7) is an NAD+-dependent deacylase implicated in cancer, known to deacetylate H3K36 and H3K18 on nucleosomes.
Purpose of the Study:
- To elucidate the structural basis of SIRT7's specificity for H3K36 and H3K18 deacylation.
- To understand how SIRT7 interacts with nucleosomes at a structural level.
Main Methods:
- Mechanism-based cross-linking strategy
- Cryo-electron microscopy (cryo-EM)
- Enzymatic and cellular assays
Main Results:
- Structures of nucleosome-bound SIRT7 were determined, revealing its unique N-terminal nucleosome-binding domain and catalytic domain interaction site.
- SIRT7 exhibits distinct binding poses for H3K36 versus H3K18, inducing structural changes in both the enzyme and nucleosome.
- The study uncovers the structural determinants of SIRT7's lysine specificity.
Conclusions:
- The findings provide a structural understanding of SIRT7's nucleosome recognition and deacylation specificity.
- Engineered SIRT7 variants with enhanced H3K18ac selectivity were developed.
- This work lays the foundation for designing small molecule modulators of SIRT7 activity.
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