Han Aidong, He Ju, Wu Yongqing, Liu Jun O, Chen Lin
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309-0215, USA.
J Mol Biol. 2005 Jan 7;345(1):91-102. doi: 10.1016/j.jmb.2004.10.033.
Class II histone deacetylases (HDACs) bind myocyte enhancer factor-2 (MEF2) and repress specific gene expression in a calcium-dependent manner. Despite their significant physiological functions in muscle, immune and neuronal cells, the mechanism of recruitment of class II HDACs by MEF2 is not well understood. Here, we have characterized the complex between the MEF2-binding motif of class II HDACs and the MADS-box/MEF2S domain of MEF2B by structural and biochemical methods. The crystal structure of a HDAC9/MEF2/DNA complex reveals that HDAC9 binds to a hydrophobic groove of the MEF2 dimer. The overall binding mode is similar to that seen in the Cabin1/MEF2/DNA complex. The detailed binding interactions at the HDAC9/MEF2 interface, however, show marked differences from those at the Cabin1/MEF2 interface. Our studies suggest a general mechanism by which class II HDACs and possibly other transcriptional co-regulators are recruited by MEF2. On the other hand, the differential binding between MEF2 and its various partners may confer specific regulatory and functional properties to MEF2 in distinct cellular processes. Such specificity provides a basis for selectively disrupting a particular MEF2/co-regulator complex by mutations or small molecules.
II类组蛋白去乙酰化酶（HDACs）与肌细胞增强因子2（MEF2）结合，并以钙依赖的方式抑制特定基因的表达。尽管它们在肌肉、免疫和神经细胞中具有重要的生理功能，但MEF2招募II类HDACs的机制仍不清楚。在这里，我们通过结构和生化方法对II类HDACs的MEF2结合基序与MEF2B的MADS盒/MEF2S结构域之间的复合物进行了表征。HDAC9/MEF2/DNA复合物的晶体结构表明，HDAC9与MEF2二聚体的疏水凹槽结合。整体结合模式与Cabin1/MEF2/DNA复合物中的相似。然而，HDAC9/MEF2界面处的详细结合相互作用与Cabin1/MEF2界面处的明显不同。我们的研究提出了一种II类HDACs以及可能其他转录共调节因子被MEF2招募的一般机制。另一方面，MEF2与其各种伙伴之间的差异结合可能在不同的细胞过程中赋予MEF2特定的调节和功能特性。这种特异性为通过突变或小分子选择性破坏特定的MEF2/共调节因子复合物提供了基础。
