Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2
Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2
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DOI：
10.1038/nature01555
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发表时间：
2003-04-17
期刊：
影响因子：
64.8
通讯作者：
Chen, L
中科院分区：
文献类型：
--
作者：
Han, AD;Pan, F;Chen, L
肌细胞增强因子-2 （myocyte enhancer factor-2, MEF2）家族转录因子在T细胞、神经细胞和肌肉细胞的发育和功能中起重要作用（1-3）。MEF2能够以钙依赖的方式与多种共抑制因子或共激活因子相关联，从而抑制或激活转录（1,4,5）。MEF2的转录抑制引起了特别的关注，因为它在心肌细胞肥厚反应中的潜在作用(6)。已经发现了几种MEF2共抑制因子，如Cabin1/Cain和II类组蛋白去乙酰化酶（hdac）（7-12）。然而，它们被MEF2募集到特定启动子的分子机制在很大程度上仍然未知。在这里，我们报道了人类MEF2B的MADS-box/MEF2S结构域在2.2埃分辨率下与转录协同抑制因子Cabin1和DNA的基序结合的晶体结构。晶体结构显示MADS盒表面有稳定折叠的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复合物的研究显示了MEF2将转录共抑制因子Cabin1和II类hdac招募到特定DNA位点的一般机制。
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(1-3). MEF2 is capable of repressing or activating transcription by association with a variety of co-repressors or co-activators in a calcium-dependent manner(1,4,5). Transcriptional repression by MEF2 has attracted particular attention because of its potential role in hypertrophic responses of cardiomyocytes(6). Several MEF2 co-repressors, such as Cabin1/Cain and class II histone deacetylases (HDACs), have been identified(7-12). 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 Angstrom 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.