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Structure of HDAC3 bound to co-repressor and inositol tetraphosphate

Abstract

Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate molecule—d-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P4)—acting as an ‘intermolecular glue’ between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P4, which may act as a regulator—potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.

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Figure 1: Structure of the HDAC3–SMRT-DAD complex.
Figure 2: Ins(1,4,5,6)P 4 binding to the HDAC3–SMRT-DAD complex.
Figure 3: Sequence conservation suggests that class I HDACs, from yeast to man, require inositol phosphates for assembly and activation.
Figure 4: Mechanism of activation of HDAC3 by binding SMRT-DAD and Ins(1,4,5,6)P4.
Figure 5: Exploring the role of Ins(1,4,5,6)P 4 in complex assembly and HDAC3 activation.

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Accession codes

Data deposits

Atomic coordinates and structure factors are deposited in the Protein Data Bank under accession number 4A69.

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Acknowledgements

We thank R. Owen and the other beamline staff at DIAMOND I24 for help with data collection; J. Goodchild for help with biochemical experiments; and S. Cowley, M. Lazar, P. Moody, L. Nagy, P. Tontonoz and S. Shears for literature and discussions. This work was supported by the Wellcome Trust (grant WT085408).

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P.J.W. expressed, purified and crystallized the protein and performed the biochemical studies. P.J.W., L.F. and J.W.R.S. performed the structural determination and wrote the paper. G.M.S. and L.F. performed early expression/purification trials in insect cells. J.W.R.S. conceived the study.

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Correspondence to John W. R. Schwabe.

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Watson, P., Fairall, L., Santos, G. et al. Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature 481, 335–340 (2012). https://doi.org/10.1038/nature10728

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