Importance of Dimer Formation of Myocardin Family Members in the Regulation of Their Nuclear Export
Importance of Dimer Formation of Myocardin Family Members in the Regulation of Their Nuclear Export
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DOI：
10.1247/csf.13001
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发表时间：
2013-01-01
影响因子：
1.5
通讯作者：
Morita, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Hayashi, Ken'ichiro;Morita, Tsuyoshi
Myocardin（Mycd）家族成员作为血清反应因子（SRF）的转录辅因子起作用。二聚体的形成是发挥其功能所必需的，卷曲螺旋结构域（CC）在其二聚化中起着关键作用。我们最近揭示了一个详细的分子机制Crm 1（exportin 1）介导的核出口。在这里，我们发现了Mycd家族成员二聚化的其他独特意义。在肌红蛋白相关转录因子A（MRTF-A）和截短Mycd的CC中引入突变导致其细胞质定位显着减少，核定位增加。根据这种亚细胞定位的变化，它们与Crm 1的结合减少。这些结果表明，Mycd家族成员的二聚化是Crm 1介导的核输出所必需的。我们最近发现，Mycd的N-末端区域由128个氨基酸组成（Mycd N128）通过中央碱性结构域（CB）与Mycd自缔合，导致掩蔽Crm 1结合位点。MRTF-A的这种自缔合是不可能的。在这项研究中，我们还揭示了Mycd的二聚化也是这种自缔合所必需的。野生型Mycd比缺乏Mycd N128的Mycd（Mycd Delta N128）更有效地激活SRF介导的转录。这些结果表明Mycd N128的两个可能的功能：1）稳定Mycd二聚体以增强SRF介导的转录和2）正调节Mycd的反式激活能力。这些发现为Mycd家族成员的功能调节提供了新的见解。
Myocardin (Mycd) family members function as a transcriptional cofactor for serum response factor (SRF). Dimer formation is necessary to exhibit their function, and the coiled-coil domain (CC) plays a critical role in their dimerization. We have recently revealed a detailed molecular mechanism for their Crm1 (exportin1)-mediated nuclear export. Here, we found other unique significances of the dimerization of Mycd family members. Introduction of mutations in the CC of myocardin-related transcription factor A (MRTF-A) and truncated Mycd resulted in significant decreases in their cytoplasmic localization and increases in their nuclear localization. In accordance with such subcellular localization changes, their binding to Crm1 were reduced. These results indicate that the dimerization of Mycd family members is necessary for their Crm1-mediated nuclear export. We have recently found that the N-terminal region of Mycd consisting of 128 amino acids (Mycd N128) self-associates to Mycd via the central basic domain (CB), resulting in masking the Crm1-binding site. Such self-association of MRTF-A would be unlikely. In this study, we also revealed that the dimerization of Mycd was also necessary for this self-association. Wild-type Mycd activated SRF-mediated transcription more potently than Mycd lacking the Mycd N128 (Mycd Delta N128) did. These results suggest two possible functions of the Mycd N128: 1) stabilization of Mycd dimer to enhance SRF-mediated transcription and 2) positive regulation of the transactivation ability of Mycd. These findings provide a new insight into the functional regulation of Mycd family members.