Structural insight into the separate roles of inositol tetraphosphate and deacetylase‐activating domain in activation of histone deacetylase 3

Abstract

Histone deacetylases (HDACs) repress transcription by deacetylating acetyllysines on specific histone tails. HDAC3 is implicated in neurodegenerative diseases, certain leukemias, and even in disrupting HIV-1 latency. A recent crystal structure of HDAC3 in complex with the deacetylase-activating domain (DAD) of its corepressor complex revealed an inositol tetraphosphate (IP4) molecule at the protein-protein interface. IP4 was shown to play an important, yet mechanistically ambiguous, role in the activity of HDAC3. The goal of this article is to explore the conformational ensemble of HDAC3 in its inactive apo state and in the presence of each or both of DAD and IP4. Using triplicate, 100 ns molecular dynamic simulations, we study the apo, ternary, and intermediate DAD-bound or IP4-bound HDAC3 states. We find that a population-shift effect is induced by the presence of each corepressor, and is most notable in the presence of both. Our results offer new insights into the change in dynamics necessary for the activation of HDAC3 and highlight the roles of IP4 and DAD in this process.

Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor

“…The essential role of K25 in DAD-binding supports the role of IP 4 as ‘intermolecular glue’ (Watson et al, 2012). Loss of deacetylase activity in K25A mutant is consistent with the undetectable HDAC3 enzyme activity in NS-DADm mice (You et al, 2013) and support the interdependence between DAD and IP 4 in activating HDAC3 enzymatic activity (Arrar et al, 2013). …”

“…The recently published structure of HDAC3 co-crystallized with a short DAD peptide reveals an inositol tetraphosphate molecule Ins(1,4,5,6)P 4 (IP 4 ) embedded at the interface between HDAC3 and DAD, which likely serves as a ‘intermolecular glue’ to stabilize the interaction (Watson et al, 2012). Binding to IP 4 and DAD triggers a conformational change in HDAC3 that makes the catalytic channel accessible to the substrate (Arrar et al, 2013; Watson et al, 2012). Consistent with this structural model, combined mutations on residues that interact with IP 4 , including Y478A in NCOR and Y470A in SMRT, completely abolish deacetylase activities of HDAC3 in mice (You et al, 2013).…”

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

“…The limited intrinsic enzymatic activity of HDAC3 is markedly enhanced by its binding to the deacetylase-activating domain (DAD) of NCoR1 or SMRT/ NCoR2 (19). IP4 helps stabilize this interaction and also triggers a conformational change in HDAC3 that makes its catalytic site more accessible to substrate (26,27). To test whether the interaction of HDAC3 with NCoR1 or SMRT/NCoR2 is required for optimal Treg function, we used mice with mutations of the DADs of both NCoR1 and SMRT/NCoR2 (28) …”

Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates

“…It is likely that the SANT domain is either “engaged” or “disengaged” from the catalytic domain of the HDAC depending upon the concentration of the inositol phosphate. Exactly the mechanism through which engaging the SANT domain activates the HDAC remains to be determined, but we and others have proposed that this involves a stabilization of the dynamics of the catalytic domain so as to open the channel to the active site of the enzyme (Arrar et al., 2012; Watson et al., 2012). …”