The protein deacetylase SIRT6 maintains cellular homeostasis through multiple pathways that include the deacetylation of histone H3 and repression of transcription. Prior work suggests that SIRT6 is associated with chromatin and can substantially reduce global levels of H3 acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we describe an exquisitely tight interaction between SIRT6 and nucleosome core particles, in which a 2:1 enzyme:nucleosome complex assembles via asymmetric binding with distinct affinities. While both SIRT6 molecules associate with the acidic patch on the nucleosome, we find that the intrinsically disordered SIRT6 C-terminus promotes binding at the higher affinity site through recognition of nucleosomal DNA. Together, multivalent interactions couple productive binding to efficient deacetylation of histones on endogenous chromatin. Unique among histone deacetylases, SIRT6 possesses the intrinsic capacity to tightly interact with nucleosomes for efficient activity.

蛋白质脱乙酰酶 SIRT6 通过多种途径维持细胞稳态，包括组蛋白 H3 脱乙酰化和转录抑制。先前的研究表明，SIRT6 与染色质相关，可以显着降低 H3 乙酰化的整体水平，但 SIRT6 如何实现这一壮举尚不清楚。在这里，我们描述了 SIRT6 和核小体核心颗粒之间极其紧密的相互作用，其中 2:1 酶：核小体复合物通过具有不同亲和力的不对称结合组装。虽然两种 SIRT6 分子都与核小体上的酸性斑块相关，但我们发现本质上无序的 SIRT6 C 末端通过识别核小体 DNA 促进在更高亲和力位点的结合。总之，多价相互作用将有效结合与内源染色质上组蛋白的有效脱乙酰化结合起来。 SIRT6 在组蛋白脱乙酰酶中是独一无二的，它具有与核小体紧密相互作用以实现高效活性的内在能力。