Year: 2016
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms11262
Institutions: University of Leicester, University of Bath, University of Oxford
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,678
Awards: The Molecular Functioning of HDAC:co-repressor complexes., Understanding the recruitment of Class I HDACs into diverse repression complexes: implications for physiological activity and therapeutic devlopment, Driving Translational Biomedical Research At The University Of Leicester, Understanding the contribution of inositol phosphate signalling to class-1 HDAC complex function, Chemical Biology of Cellular Signalling using Polyphosphate Messengers., G6700115685, G7398050237, G761486364, G8482136486, Understanding the essential requirement for HDAC1 and HDAC2 in tissue development and homeostasis: implications for disease and therapy.
OpenAlex ID: W2320230258