Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex

Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing transcription and regulating the transcriptional output of each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs. SIN3B is a histone deacetylase part of the holo-SIN3 complex. Here by cryo-electron microscopy we unveil the assembly, activation, specificity, and substrate recognition of the human SIN3B histone deacetylase complex.

Automated summary

The study reveals the structure and mechanism of action of the SIN3B histone deacetylase. SIN3B stimulates catalysis by contacting the allosteric basic patch of the deacetylase and guides specific deacetylation through interaction with the substrate receptor subunit. These findings provide insights for future drug designs.