It consists of an eight-stranded parallel beta-sheet surrounded by a bunch of a-helices. The active site lies at the base of a tunnel leading from the surface of the protein. This enzyme is always found in complexes containing corepressors of nuclear receptor and acts as one of the functional groups. These corepressors include NCOR1 and NCOR2 (also called silencing mediator of retinoid and thyroid receptors, or SMRT). Both of the complexes they formed are transcriptional coregulatory proteins mediating the repression function of unliganded nuclear hormone receptors and other classes of transcriptional repressors. The enzymatic activity of HDAC3 is one of the potential mechanisms of conveying a repression signal when the complex is recruited to a target gene. Notably, NCOR1 and SMRT binding to HDAC3 are indispensable for HDAC3 activity, without which HDAC3 could not perform its function properly. These two complexes interact with HDAC3 through multiple domains, but only the regions containing a SANT motif and a unique N-terminal helical extension can activate the catalytic function of the HDAC3, therefore they together are named as deacetylase-activating domain (DAD). Other studies show that both N- and C- termini of HDAC3 are necessary for interaction with SMRT DAD. Besides that, D-myo-inositol-1,4,5,6-tetrakisphosphate, acting like a …show more content…
The normal form of Huntingtin gene (Htt) contains 6-35 glutamine residues. HDAC3, abundantly expresses in the brain, directly binds to it with this short polyglutamine (pQ) and this interaction normalizes the intrinsic neurotoxic property of HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, resulting neuron death and cause disease. However, HDAC3 inhibitor interacts with nuclear and cytoplasmic HDAC3 differently such that inhibition could be beneficial in accelerating cytoplasmic Htt-ex1 pQ aggregation degradation, but it inhibits the degradation of nuclear Htt-ex1 aggregates, which turns back to impair the function of HDAC3 further, and then the activity of proteasome through some unknown signal pathway.