title: Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering, protein-protein docking, peptide docking and molecular dynamics simulations.
abstract: The Klotho is known as lifespan enhancing protein involved in antagonizing the effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted exposure of Wnt proteins to the cell can cause stem and progenitor cell senescence, which may lead to aging. Keeping in mind the importance of Klotho in Wnt signaling, in silico approaches have been applied to study the important interactions between Klotho and Wnt3 and Wnt3a (wingless-type mouse mammary tumor virus (MMTV) integration site family members 3 and 3a). The main aim of the study is to identify important residues of the Klotho that help in designing peptides which can act as Wnt antagonists. For this aim, a protein engineering study is performed for Klotho, Wnt3 and Wnt3a. During the theoretical analysis of homology models, unexpected role of number of disulfide bonds and secondary structure elements has been witnessed in case of Wnt3 and Wnt3a proteins. Different in silico experiments were carried out to observe the effect of correct number of disulfide bonds on 3D protein models. For this aim, total of 10 molecular dynamics (MD) simulations were carried out for each system. Based on the protein-protein docking simulations of selected protein models of Klotho with Wnt3 and Wnt3a, different peptides derived from Klotho have been designed. Wnt3 and Wnt3a proteins have three important domains: Index finger, N-terminal domain and a patch of ∼10 residues on the solvent exposed surface of palm domain. Protein-peptide docking of designed peptides of Klotho against three important domains of palmitoylated Wnt3 and Wnt3a yields encouraging results and leads better understanding of the Wnt protein inhibition by proposed Klotho peptides. Further in vitro studies can be carried out to verify effects of novel designed peptides as Wnt antagonists.
authors: a Department of Biophysics, School of Medicine , Bahcesehir University (BAU) , Istanbul , Turkey.|b Department of Biosciences , COMSATS Institute of Information Technology (CIIT) , Islamabad , Pakistan.
authors: Shaher Bano
authors: SB
authors: Mirza
authors: a Department of Biophysics, School of Medicine , Bahcesehir University (BAU) , Istanbul , Turkey.
authors: Ramin
authors: R
authors: Ekhteiari Salmas
authors: b Department of Biosciences , COMSATS Institute of Information Technology (CIIT) , Islamabad , Pakistan.
authors: M Qaiser
authors: MQ
authors: Fatmi
authors: a Department of Biophysics, School of Medicine , Bahcesehir University (BAU) , Istanbul , Turkey.
authors: Serdar
authors: S
authors: Durdagi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005966:Glucuronidase / Q000737:chemistry*; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D015202:Protein Engineering; D060508:Wnt3 Protein / Q000037:antagonists & inhibitors*
chemical_list: D010455:Peptides; C555507:WNT3 protein, human; D060508:Wnt3 Protein; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Homology modeling; Klotho; Wnt3; Wnt3a; molecular dynamics (MD) simulations; peptide design; protein engineering; protein–protein docking