title: Rational design of YAP WW1 domain-binding peptides to target TGFβ/BMP/Smad-YAP interaction in heterotopic ossification.
abstract: The transforming growth factor-β/bone morphogenic protein/Smad signaling pathway has been raised as a new and promising therapeutic target of heterotopic ossification, which is mediated by recruitment of transcription coactivator Yes-associated protein (YAP) to Smad. Here, we described a successful integration of computational modeling and experimental assay to rationally design novel peptide aptamers to disrupt YAP-Smad interaction by targeting YAP WW1 domain. In the protocol, a computational genetic evolution strategy was used to improve a population of potential YAP WW1-binding peptides generated from the YAP-recognition site in Smad protein, from which several promising peptides were selected and their affinities toward YAP WW1 domain were determined using binding assay. In addition, a high-activity peptide was further optimized based on its complex structure with YAP WW1 domain to derive a number of derivative peptides with higher binding potency to the domain. We also found that a strong YAP WW1 binder should have a negatively charged N-terminus, a positively charged C-terminus and a nonpolar core to match the electrostatic distribution pattern in peptide-binding pocket of YAP WW1 domain, which may also form additional nonbonded interactions such as hydrogen bond, salt bridge and π-π stacking to confer stability and specificity for the domain-peptide recognition.
authors.affiliation: Department of Orthopedics, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China.
authors.forename: Shenghe
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China.
authors.forename: Luyuan
authors.initials: L
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D015195:Drug Design; D004735:Energy Transfer; D019143:Evolution, Molecular; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009999:Ossification, Heterotopic / Q000188:drug therapy / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D055672:Static Electricity; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D010750:Phosphoproteins; D051785:Smad Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: TGFβ/BMP/Smad signaling pathway; YAP WW1 domain; heterotopic ossification; peptide