Disease Area Oncology, Novartis Institutes for Biomedical Research, CH-4056, Basel, Switzerland.
Disease Area Oncology, Novartis Institutes for Biomedical Research, CH-4056, Basel, Switzerland.
Arch Biochem Biophys. 2024 Oct;760:110136. doi: 10.1016/j.abb.2024.110136. Epub 2024 Aug 23.
The TEAD transcription factors are the final effectors of the Hippo pathway, and to exert their transcriptional activity they need to interact with other proteins. The three paralogous vestigial-like proteins VGLL1, VGLL2 and VGLL3 bind to TEAD via a conserved short linear sequence, the Tondu motif. The TEAD-binding domain of human VGLL2 contains in addition an Ω-loop, which is also present in Vg (vestigial) from arthropods and the YAP proteins, another family of TEAD interactors. In this report, using the available structural data, we study the amino acid sequence of the TEAD-binding domain of more than 2400 putative VGLL proteins from vertebrates. This analysis shows a strong link between sequence conservation and functional role for the residues from the Tondu motif. It also reveals that one protein sequence containing both a Tondu motif and an Ω-loop is present in most (if not all) vertebrate species. This suggests that there is a selective pressure to keep a VGLL paralog with a functional Ω-loop in vertebrates. Finally, this study identifies, particularly in mammals, variants of VGLL2 and VGLL3 with an altered TEAD-binding domain suggesting that they may have a different biological function than their homologs.
TEAD 转录因子是 Hippo 通路的最终效应物，为发挥其转录活性，它们需要与其他蛋白质相互作用。三个同源的 vestigial 样蛋白 VGLL1、VGLL2 和 VGLL3 通过一个保守的短线性序列 Tondu 基序与 TEAD 结合。人类 VGLL2 的 TEAD 结合域还包含一个 Ω 环，该环也存在于节肢动物的 Vg（vestigial）和 YAP 蛋白中，YAP 蛋白是 TEAD 的另一个相互作用蛋白家族。在本报告中，我们利用现有的结构数据，研究了超过 2400 种脊椎动物假定 VGLL 蛋白的 TEAD 结合域的氨基酸序列。该分析表明，Tondu 基序的残基的序列保守性与其功能之间存在很强的联系。它还表明，在大多数（如果不是全部）脊椎动物物种中都存在一种既包含 Tondu 基序又包含 Ω 环的蛋白质序列。这表明在脊椎动物中存在保持具有功能性 Ω 环的 VGLL 同源物的选择压力。最后，本研究鉴定出，特别是在哺乳动物中，VGLL2 和 VGLL3 的变体具有改变的 TEAD 结合域，表明它们可能具有与其同源物不同的生物学功能。
