Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, People's Republic of China.
Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, People's Republic of China; Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, People's Republic of China.
J Theor Biol. 2019 Jul 7;472:27-35. doi: 10.1016/j.jtbi.2019.04.009. Epub 2019 Apr 10.
Transcriptional enhancer activation domain (TEAD) proteins are the downstream transcriptional factor of the Hippo pathway. The transcription co-activators Yes-associated protein (YAP) and its paralog transcription co-activators with PDZ-binding motif (TAZ), binding to TEAD to promote transcription of genes in cell proliferation and anti-apoptosis, are key effectors of the Hippo pathway. TEAD4, one member of TEAD proteins, is specifically required in embryo implantation. The recently reported crystal structure of TEAD4-TAZ complex (PDB Code 5GN0) in mouse reveals that the interactions between the two helices of YAP/TAZ and TEAD4 are highly conserved. Point mutation of the residue Tyr422 of TEAD4 protein would disrupt the relevant hydrogen bond and even abolish the interaction. However, detailed information affected by the mutation at the atom level are still unrevealed. Molecular dynamics (MD) simulations and the molecular mechanics/Generalized-Born surface area (MM/GBSA) free energy calculations were used to explore the effects of mutation Tyr422Ala on the structural flexibility and conformational dynamics. The non-polar interactions play an indispensable role in the binding process of TEAD4 and YAP/TAZ. The helices α1 and α2 of YAP/TAZ provide a primary function to anchor YAP/TAZ well bound to TEAD4. The mutation Tyr422Ala disrupts the hydrogen-bonding network but do not obviously influence the secondary structure stability of TEAD4. The binding conformation of YAP/TAZ distorted by decreased non-polar interaction and the lost hydrogen bonds would lead to reduced interaction activity. The present study would provide important insights into the structure-function relationships of TEAD protein and give a new explanation for the affinity of YAP/TAZ with TEAD.
转录增强子激活结构域（TEAD）蛋白是 Hippo 通路的下游转录因子。转录共激活因子 Yes 相关蛋白（YAP）及其 PDZ 结合基序（TAZ）的同源物，与 TEAD 结合，促进细胞增殖和抗细胞凋亡相关基因的转录，是 Hippo 通路的关键效应因子。TEAD 蛋白家族的成员之一 TEAD4，在胚胎着床中具有特异性。最近报道的小鼠 TEAD4-TAZ 复合物的晶体结构（PDB 码 5GN0）表明，YAP/TAZ 的两个螺旋与 TEAD4 之间的相互作用高度保守。TEAD4 蛋白残基 Tyr422 的点突变会破坏相关氢键，甚至使相互作用丧失。然而，突变在原子水平上影响的详细信息仍未被揭示。分子动力学（MD）模拟和分子力学/广义 Born 表面积（MM/GBSA）自由能计算被用来研究突变 Tyr422Ala 对结构柔韧性和构象动力学的影响。非极性相互作用在 TEAD4 和 YAP/TAZ 的结合过程中起着不可或缺的作用。YAP/TAZ 的α1 和α2 螺旋提供了一个主要功能，将 YAP/TAZ 很好地锚定在 TEAD4 上。突变 Tyr422Ala 破坏了氢键网络，但对 TEAD4 的二级结构稳定性没有明显影响。由于非极性相互作用减少和失去氢键，YAP/TAZ 的结合构象发生扭曲，导致相互作用活性降低。本研究将为 TEAD 蛋白的结构-功能关系提供重要的见解，并为 YAP/TAZ 与 TEAD 的亲和力提供新的解释。
