Crystal structure of the DNA-binding domain of Myelin-gene Regulatory Factor.
Crystal structure of the DNA-binding domain of Myelin-gene Regulatory Factor.
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髓磷脂基因调节因子 DNA 结合域的晶体结构
DOI：
10.1038/s41598-017-03768-9
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发表时间：
2017-06-16
影响因子：
4.6
通讯作者：
Shi N
中科院分区：
文献类型：
--
作者：
Zhen X;Li B;Hu F;Yan S;Meloni G;Li H;Shi N
髓鞘基因调节因子（Myelin-gene Regulatory Factor，MyRF）是控制少突胶质细胞髓鞘形成和发育的主要转录因子之一，对脑功能的发挥起着重要作用。MyRF的N-末端含有富含脯氨酸的区域和DNA结合结构域（DBD），其从ER膜自切割，然后进入细胞核参与髓磷脂基因的转录调节。在这里，我们报告的MyRF DBD的晶体结构。它显示出Ig折叠样结构，其由两个具有7条主链的反平行β-折叠组成，相互包装，形成β-三明治。与其同系物Ndt 80相比，MyRF具有较小且不太复杂的DBD，缺乏螺旋和核心外的大环。结构比对表明，MyRF DBD具有较少的相互作用位点与DNA比Ndt 80，可能只结合在DNA的大沟。此外，该结构揭示了三聚体组装，与先前的报告一致，即MyRF DBD作为三聚体发挥作用。根据该结构设计的突变体干扰了三聚体的形成，但不影响自切割反应。这表明MyRF的自切割反应的激活不依赖于其N-末端DBD同源三聚体的存在。本文报道的结构将有助于理解MyRF在髓鞘形成和发育中的重要作用的分子机制。
Myelin-gene Regulatory Factor (MyRF) is one of the master transcription factors controlling myelin formation and development in oligodendrocytes which is crucial for the powerful brain functions. The N-terminal of MyRF, which contains a proline-rich region and a DNA binding domain (DBD), is auto-cleaved from the ER membrane, and then enters the nucleus to participate in transcription regulation of the myelin genes. Here we report the crystal structure of MyRF DBD. It shows an Ig-fold like architecture which consists of two antiparallel β-sheets with 7 main strands, packing against each other, forming a β-sandwich. Compared to its homolog, Ndt80, MyRF has a smaller and less complex DBD lacking the helices and the big loops outside the core. Structural alignment reveals that MyRF DBD possess less interaction sites with DNA than Ndt80 and may bind only at the major groove of DNA. Moreover, the structure reveals a trimeric assembly, agreeing with the previous report that MyRF DBD functions as a trimer. The mutant that we designed based on the structure disturbed trimer formation, but didn’t affect the auto-cleavage reaction. It demonstrates that the activation of self-cleavage reaction of MyRF is independent of the presence of its N-terminal DBD homotrimer. The structure reported here will help to understand the molecular mechanism underlying the important roles of MyRF in myelin formation and development.