A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.
A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.
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DOI：
10.1016/j.jmb.2016.03.008
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发表时间：
2016-06-19
影响因子：
5.6
通讯作者：
Veeraraghavan S
中科院分区：
文献类型：
--
作者：
Lee DS;Vonrhein C;Albarado D;Raman CS;Veeraraghavan S
TEA结构域转录因子(TEAD)是真核生物正常发育所必需的，是河马肿瘤抑制通路的下游效应物。虽然我们早期的工作利用溶液核磁共振光谱建立了高度保守的DNA结合域的三维结构，但调节DNA结合活性的结构基础仍不清楚。在这里，我们介绍了一个含有截短L1环的TEA结构域突变体ΔL1 tead DBD的X射线晶体结构和活性。出人意料的是，ΔL1 TEAD DBD的三维结构揭示了一种螺旋交换的同源二聚体，其中螺旋1在单体之间交换。此外，结构域互换的二聚体中的每个三螺旋束都是MYB样结构域的结构同源。我们的DNA结合活性研究表明，尽管ΔL1 TEAD DBD形成的三螺旋束足以与分离的M-CAT样DNA元件结合，但多聚体形式缺乏与DNA重复元件的协同结合，表明L1环有助于TEAD的DNA结合活性。这些结果表明，单体形式和结构域交换形式之间的转换可能调节TEAD蛋白的DNA选择性。
TEA domain transcription factors (TEAD) are essential for normal development of eukaryotes and are the downstream effectors of the Hippo tumor suppressor pathway. Whereas our earlier work established the three-dimensional structure of the highly conserved DNA binding domain using solution NMR spectroscopy, the structural-basis for regulating the DNA binding activity remains unknown. Here, we present the X-ray crystallographic structure and activity of a TEA domain mutant containing a truncated L1 loop, ΔL1 TEAD DBD. Unexpectedly, the three-dimensional structure of the ΔL1 TEAD DBD reveals a helix-swapped homodimer wherein helix 1 is swapped between monomers. Furthermore, each three-helix bundle in the domain-swapped dimer is a structural homolog of MYB-like domains. Our investigations of the DNA binding activity reveal that although the formation of the three-helix bundle by the ΔL1 TEAD DBD is sufficient for binding to an isolated M-CAT-like DNA element, multimeric forms are deficient for cooperative binding to tandemly duplicated elements, indicating that the L1 loop contributes to the DNA binding activity of TEAD. These results suggest that switching between monomeric and domain-swapped forms may regulate DNA selectivity of TEAD proteins.