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

Peter J. Watson, Christopher J. Millard, Andrew M. Riley, Naomi S. Robertson, Lyndsey C. Wright, Himali Y. Godage, Shaun M. Cowley, Andrew G. Jamieson, Barry V. L. Potter and John W. R. Schwabe ()
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Peter J. Watson: Henry Wellcome Laboratories of Structural Biology, University of Leicester
Christopher J. Millard: Henry Wellcome Laboratories of Structural Biology, University of Leicester
Andrew M. Riley: University of Bath
Naomi S. Robertson: University of Leicester
Lyndsey C. Wright: Henry Wellcome Laboratories of Structural Biology, University of Leicester
Himali Y. Godage: University of Bath
Shaun M. Cowley: Henry Wellcome Laboratories of Structural Biology, University of Leicester
Andrew G. Jamieson: University of Leicester
Barry V. L. Potter: University of Bath
John W. R. Schwabe: Henry Wellcome Laboratories of Structural Biology, University of Leicester

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11262

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