The most downstream elements of the Hippo pathway, the TEAD transcription factors, are regulated by several cofactors, such as Vg/VGLL1-3. Earlier findings on human VGLL1 and here on human VGLL3 show that these proteins interact with TEAD via a conserved amino acid motif called the TONDU domain. Surprisingly, our studies reveal that the TEAD-binding domain of Drosophila Vg and of human VGLL2 is more complex and contains an additional structural element, an Ω-loop, that contributes to TEAD binding and in vivo function. To explain this unexpected structural difference between proteins from the same family, we propose that, after the genome-wide duplications at the origin of vertebrates, the Ω-loop present in an ancestral VGLL gene has been lost in some VGLL variants. These findings illustrate how structural and functional constraints can guide the evolution of transcriptional cofactors to preserve their ability to compete with other cofactors for binding to transcription factors.

中文翻译：

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Vg / VGLL1-3蛋白与TEAD转录因子相互作用的进化新视角

Hippo途径的最下游元件，即TEAD转录因子，受多种辅助因子（例如Vg / VGLL1-3）调节。关于人VGLL1和这里的人VGLL3的早期发现表明，这些蛋白质通过称为TONDU域的保守氨基酸基序与TEAD相互作用。出人意料的是，我们的研究表明果蝇Vg和人VGLL2的TEAD结合结构域更为复杂，并包含一个额外的结构元件Ω环，有助于TEAD结合和体内功能。为了解释同一家族蛋白质之间这种意想不到的结构差异，我们建议在脊椎动物起源的全基因组复制后，祖先的VGLL基因中存在的Ω环在某些VGLL变体中已经丢失。