Han Aidong, Pan Fan, Stroud James C, Youn Hong-Duk, Liu Jun O, Chen Lin
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215, USA.
Nature. 2003 Apr 17;422(6933):730-4. doi: 10.1038/nature01555.
The myocyte enhancer factor-2 (MEF2) family of transcription factors has important roles in the development and function of T cells, neuronal cells and muscle cells. MEF2 is capable of repressing or activating transcription by association with a variety of co-repressors or co-activators in a calcium-dependent manner. Transcriptional repression by MEF2 has attracted particular attention because of its potential role in hypertrophic responses of cardiomyocytes. Several MEF2 co-repressors, such as Cabin1/Cain and class II histone deacetylases (HDACs), have been identified. However, the molecular mechanism of their recruitment to specific promoters by MEF2 remains largely unknown. Here we report a crystal structure of the MADS-box/MEF2S domain of human MEF2B bound to a motif of the transcriptional co-repressor Cabin1 and DNA at 2.2 A resolution. The crystal structure reveals a stably folded MEF2S domain on the surface of the MADS box. Cabin1 adopts an amphipathic alpha-helix to bind a hydrophobic groove on the MEF2S domain, forming a triple-helical interaction. Our studies of the ternary Cabin1/MEF2/DNA complex show a general mechanism by which MEF2 recruits transcriptional co-repressor Cabin1 and class II HDACs to specific DNA sites.
转录因子肌细胞增强因子2（MEF2）家族在T细胞、神经元细胞和肌肉细胞的发育及功能中发挥着重要作用。MEF2能够通过以钙依赖的方式与多种共抑制因子或共激活因子结合来抑制或激活转录。MEF2介导的转录抑制因其在心肌细胞肥大反应中的潜在作用而备受关注。已鉴定出几种MEF2共抑制因子，如Cabin1/Cain和II类组蛋白去乙酰化酶（HDAC）。然而，MEF2将它们招募至特定启动子的分子机制仍 largely未知。在此，我们报道了人MEF2B的MADS盒/MEF2S结构域与转录共抑制因子Cabin1的一个基序及DNA结合的晶体结构，分辨率为2.2埃。该晶体结构揭示了在MADS盒表面稳定折叠的MEF2S结构域。Cabin1采用两亲性α螺旋结合MEF2S结构域上的一个疏水凹槽，形成三螺旋相互作用。我们对三元Cabin1/MEF2/DNA复合物的研究展示了MEF2将转录共抑制因子Cabin1和II类HDAC招募至特定DNA位点的一般机制。
