Moreno-Yruela Carlos, Ekundayo Babatunde E, Foteva Polina N, Ni Dongchun, Calvino-Sanles Esther, Stahlberg Henning, Fierz Beat
Laboratory of Biophysical Chemistry of Macromolecules (LCBM), Institute of Chemical Sciences and Engineering (ISIC), School of Basic Sciences (SB), EPFL, Lausanne, Switzerland.
Laboratory of Biological Electron Microscopy (LBEM), Institute of Physics (IPHYS), School of Basic Sciences (SB), EPFL, Lausanne, Switzerland.
Nat Commun. 2025 Feb 4;16(1):1328. doi: 10.1038/s41467-025-56529-y.
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.
染色质修饰酶作用于组蛋白内不同的残基，以微调基因表达谱。SIRT7是一种NAD依赖的去乙酰化酶，在癌症中常失调，它在核小体内以高特异性使组蛋白H3赖氨酸36（H3K36）或H3K18去乙酰化。在此，我们报告了与核小体结合的SIRT7的结构，并结合基于机制的交联策略、冷冻电镜以及酶学和细胞分析，揭示了其对H3K36和K18去乙酰化特异性的结构基础。我们表明，SIRT7的N端代表一个独特的、延伸的核小体结合结构域，跨越核小体表面到达酸性斑块。催化结构域在H3尾部出口位点结合，与核小体的两个DNA螺旋相互作用。与H3K18相比，与H3K36结合需要结合姿势的改变，并导致SIRT7和核小体的结构变化。这些结构揭示了赖氨酸特异性的基础，使我们能够改造SIRT7以增强对H3K18ac的选择性，并为小分子调节剂的开发提供了基础。
