人类沉默信息调节因子6-核小体复合物的冷冻电镜结构

Cryo-EM structure of the human Sirtuin 6-nucleosome complex.

作者信息

Chio Un Seng, Rechiche Othman, Bryll Alysia R, Zhu Jiang, Feldman Jessica L, Peterson Craig L, Tan Song, Armache Jean-Paul

机构信息

Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.

The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.

出版信息

bioRxiv. 2023 Mar 18:2023.03.17.533206. doi: 10.1101/2023.03.17.533206.

DOI:10.1101/2023.03.17.533206

PMID:36993468

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10055229/

Abstract

UNLABELLED

Sirtuin 6 (SIRT6) is a multifaceted protein deacetylase/deacylase and a major target for small-molecule modulators of longevity and cancer. In the context of chromatin, SIRT6 removes acetyl groups from histone H3 in nucleosomes, but the molecular basis for its nucleosomal substrate preference is unknown. Our cryo-electron microscopy structure of human SIRT6 in complex with the nucleosome shows that the catalytic domain of SIRT6 pries DNA from the nucleosomal entry-exit site and exposes the histone H3 N-terminal helix, while the SIRT6 zinc-binding domain binds to the histone acidic patch using an arginine anchor. In addition, SIRT6 forms an inhibitory interaction with the C-terminal tail of histone H2A. The structure provides insights into how SIRT6 can deacetylate both H3 K9 and H3 K56.

TEASER

The structure of the SIRT6 deacetylase/nucleosome complex suggests how the enzyme acts on both histone H3 K9 and K56 residues.

摘要

未标记

沉默调节蛋白6（SIRT6）是一种多功能蛋白质脱乙酰酶/去酰基酶，是长寿和癌症小分子调节剂的主要靶点。在染色质环境中，SIRT6从核小体中的组蛋白H3上去除乙酰基，但其核小体底物偏好的分子基础尚不清楚。我们解析的人SIRT6与核小体复合物的冷冻电镜结构表明，SIRT6的催化结构域从核小体的进出位点撬开DNA并暴露组蛋白H3的N端螺旋，而SIRT6的锌结合结构域使用精氨酸锚定与组蛋白酸性补丁结合。此外，SIRT6与组蛋白H2A的C端尾巴形成抑制性相互作用。该结构为SIRT6如何使H3 K9和H3 K56去乙酰化提供了见解。