Journal Article

Insights into the activation mechanism of class I HDAC complexes by inositol phosphates

Millard, Christopher J., Potter, Barry V. L., Godage, Himali Y., Robertson, Naomi S., Schwabe, John W. R., Watson, Peter J., Wright, Lyndsey C., Jamieson, Andrew G., Riley, Andrew M., Cowley, Shaun M.

2016

Overview

Histone deacetylases (HDACs) 1, 2 and 3 form the catalytic subunit of several large transcriptional repression complexes. Unexpectedly, the enzymatic activity of HDACs in these complexes has been shown to be regulated by inositol phosphates, which bind in a pocket sandwiched between the HDAC and co-repressor proteins. However, the actual mechanism of activation remains poorly understood. Here we have elucidated the stereochemical requirements for binding and activation by inositol phosphates, demonstrating that activation requires three adjacent phosphate groups and that other positions on the inositol ring can tolerate bulky substituents. We also demonstrate that there is allosteric communication between the inositol-binding site and the active site. The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests a molecular basis of substrate recognition, and an entropically driven allosteric mechanism of activation. Class I histone deacetylase complexes can be activated by inositol phosphates. Here, the authors investigate the stereochemical requirements for activation; use the crystal structure to understand substrate recognition, and suggest an entropically driven mechanism of allostery.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 631/45/535 / 631/45/607/1164 / 631/57/2272 / 82 / Allosteric Regulation / Binding Sites / Biology / Catalytic Domain / Crystallography, X-Ray / Enzymatic activity / Enzyme Activation - drug effects / Enzymes / Epigenetics / HEK293 Cells / Histone Deacetylase 1 - chemistry / Histone Deacetylase 1 - genetics / Histone Deacetylase 1 - metabolism / Histone Deacetylases - chemistry / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Humanities and Social Sciences / Humans / Inositol Phosphates - chemistry / Inositol Phosphates - metabolism / Molecular Docking Simulation / multidisciplinary / Multiprotein Complexes - chemistry / Multiprotein Complexes - genetics / Multiprotein Complexes - metabolism / Peptides / Phosphates / Protein Binding / Protein Domains / Science / Science (multidisciplinary) / Scientific imaging