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Rational design of YAP WW1 domain‐binding peptides to target TGFβ/BMP/Smad–YAP interaction in heterotopic ossification
Author(s) -
Chen Dong,
Liu Shenghe,
Zhang Wen,
Sun Luyuan
Publication year - 2015
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2824
Subject(s) - smad , peptide , biology , biophysics , biochemistry , materials science , microbiology and biotechnology , transforming growth factor
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. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.