The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite transactivation mechanism
The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite transactivation mechanism
复制标题
DOI：
10.1093/nar/gkz523
复制
发表时间：
2019-07-26
影响因子：
14.9
通讯作者：
Lefebvre, Veronique
中科院分区：
文献类型：
--
作者：
Haseeb, Abdul;Lefebvre, Veronique
SOX8、SOX9和SOX10组成SOXE转录因子组。它们在许多谱系中控制着细胞的命运和分化，而它们活性受损的突变会导致严重的疾病，包括钟状核发育不良(SOX9)、性别决定障碍(SOX8和SOX9)和瓦登堡-沙阿综合征(SOX10)。然而，对它们的作用模式的不完全了解限制了对疾病的理解。我们在这里发现，这些蛋白质共享一个两部分的反式激活机制，即蛋白质中间的一个反式激活域()与一个C末端的反式激活域(TAC)协同作用。由两亲性的α-螺旋组成，预计会形成一个蛋白结合口袋，并与许多转录因子中描述的最小反式激活基序(9-AA-TAD)重叠。一个9-AA-TAD序列包括一个进化上保守且功能所需的E Phi[D/E]QY Phi基序。SOXF蛋白(SOX7、SOX17和SOX18)包含一个相同的基序，表明从已经具有该基序的共同祖先进化而来，而TAC和其他反式激活的SOX蛋白只具有远程相关的基序。这个SOXE/SOXF特异基序中的错义变体在对照组中很少见，但在癌症中已经被检测到，支持它在发育和生理上的重要性。通过深化对SOXE蛋白中央反式激活功能潜在机制的理解，这些发现应该有助于进一步破译对发育和健康至关重要的分子网络，以及疾病中的调节失调。
SOX8, SOX9 and SOX10 compose the SOXE transcription factor group. They govern cell fate and differentiation in many lineages, and mutations impairing their activity cause severe diseases, including campomelic dysplasia (SOX9), sex determination disorders (SOX8 and SOX9) and Waardenburg-Shah syndrome (SOX10). However, incomplete knowledge of their modes of action limits disease understanding. We here uncover that the proteins share a bipartite transactivation mechanism, whereby a transactivation domain in the middle of the proteins (TAM) synergizes with a C-terminal one (TAC). TAM comprises amphipathic alpha-helices predicted to form a protein-binding pocket and overlapping with minimal transactivation motifs (9-aa-TAD) described in many transcription factors. One 9-aa-TAD sequence includes an evolutionarily conserved and functionally required E Phi[D/E]QY Phi motif. SOXF proteins (SOX7, SOX17 and SOX18) contain an identical motif, suggesting evolution from a common ancestor already harboring this motif, whereas TAC and other transactivating SOX proteins feature only remotely related motifs. Missense variants in this SOXE/SOXF-specific motif are rare in control individuals, but have been detected in cancers, supporting its importance in development and physiology. By deepening understanding of mechanisms underlying the central transactivation function of SOXE proteins, these findings should help further decipher molecular networks essential for development and health and dysregulated in diseases.