Molecular dynamics simulations study of influence of Tyr422Ala mutation on transcriptional enhancer activation domain...

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.