Structure of HDAC3 bound to co-repressor and inositol tetraphosphate

Abstract

SummaryHistone 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 to corepressor complexes. We report the first structure of an HDAC:corepressor complex - HDAC3 with the deacetylase-activation-domain (DAD) from the SMRT corepressor. 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, 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 man and opens novel therapeutic opportunities.

Arginine Transcriptional Response Does Not Require Inositol Phosphate Synthesis

“…These considerations are supported by the discovery that histone deacetylase polypeptides from Tetrahymena and Paramecium possess an inositol-polyphosphate kinase domain similar to Arg82 (56). In addition, inositol tetrakisphosphate (a product of IPMK) has recently been shown to aid in the interaction of histone deacetylase 3 with a transcriptional corepressor (NCOR2) (57). This opens up the possibility that the catalytic activity of IPMK could play a subsidiary role in protein-protein interaction influencing gene transcription.…”

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

“…We posit that the solvent-exposed phosphate groups of PIP 3 together with the stabilized surface loops function as an important regulatory site, forming a new molecular docking surface. This mechanism is analogous to the bridging functions of soluble inositols (28) or to membrane-bound PIP 3 in mediating protein-lipid interactions at the plasma membrane. Candidate binding partners that could dock to this nuclear protein-lipid complex might include the large group of nuclear proteins shown to bind directly to phosphoinositol phosphate head groups (29) or to contain pleckstrin-homology (PH)-domains (30,31).…”

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction

“…Recently, transcriptional repressive functions have been implicated for inositol 1,4,5,6-tetrakisphosphate (39). In a crystal structure of histone deacetylase 3 (HDAC3) in complex with the deacetylase activating domain (DAD) domain of nuclear receptor co-repressor/silencing mediator for retinoid or thyroid-hormone receptors (NCoR/SMRT), inositol 1,4,5,6-tetrakisphosphate localizes at the interface of these two proteins and stimulates HDAC catalytic activity.…”