title: The TEAD4-YAP/TAZ protein-protein interaction: expected similarities and unexpected differences.
abstract: The Hippo pathway controls cell homeostasis, and its deregulation can lead to human diseases. In this pathway, the YAP and TAZ transcriptional cofactors play a key role in stimulating gene transcription through their interaction with the TEAD transcriptional factors. Our study of YAP and TAZ peptides in biochemical and biophysical assays shows that both proteins have essentially the same affinity for TEAD. Molecular modeling and structural biology data suggest that they also bind to the same site on TEAD. However, this apparent similarity hides differences in the ways in which the two proteins interact with TEAD. The secondary structure elements of their TEAD binding site do not contribute equally to the overall affinity, and critical interactions with TEAD are made through different residues. This convergent optimization of the YAP/TAZ TEAD binding site suggests that the similarity in the affinities of binding of YAP to TEAD and of TAZ to TEAD is important for Hippo pathway functionality.
authors.affiliation: Disease Area Oncology, Novartis Institutes for Biomedical Research, 141 Klybeckstrasse, 4057 Basel, Switzerland.
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Hau
authors.forename: Dirk
authors.initials: D
authors.lastname: Erdmann
authors.forename: Yannick
authors.initials: Y
authors.lastname: Mesrouze
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Patrizia
authors.initials: P
authors.lastname: Fontana
authors.forename: Catherine
authors.initials: C
authors.lastname: Zimmermann
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmelzle
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
mesh_terms: D000217:Acyltransferases; D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000090683:Hippo Signaling Pathway; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D010455:Peptides; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; TAZ; TEAD; YAP; omega loops; peptides; protein-protein interactions