title: Targeting Yes-associated Protein with Evolved Peptide Aptamers to Disrupt TGF-β Signaling Pathway: Therapeutic Implication for Bone Tumor.
abstract: The binding of transcription coactivator Yes-associated protein (YAP) to Smad transcription factors is an important event in activating transforming growth factor-β (TGF-β) signaling pathway, which is involved in the tumorigenicity and metastasis of bone tumor. Design of peptide aptamers to disrupt YAPSmad interaction has been established as a promising approach for bone tumor therapy. Here, an evolution strategy was used to optimize Smad-derived peptides for high potency binding to YAP WW2 domain, resulting in an improved peptide population, from which those high-scoring candidates were characterized rigorously using molecular dynamics (MD) simulations and interaction free energy calculations. With the computational protocol we were able to generate a number of potential domain binders, which were then substantiated by using fluorescence spectroscopy assay. Subsequently, the complex structure of YAP WW2 domain with a high-affinity peptide was modeled and examined in detail, which was then used to guide structure-based peptide optimization to obtain several strong domain binders. Structural and energetic analysis revealed that electrostatic complementarity is primarily responsible for domainpeptide recognition, while other nonbonded interactions such as hydrogen bonding and salt bridges can contribute significantly to the recognition specificity.
authors.affiliation: Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200433, China, Tel: +86 21 64369675.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Ji
authors.affiliation: Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200433, China, Tel: +86 21 64369675. yanggddong@126.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001859:Bone Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000072417:Protein Domains; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010455:Peptides; D010750:Phosphoproteins; D051785:Smad Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: TGF-β signaling; Yes-associated protein; bone tumor; peptide aptamer