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Expediting dynamics approach to understand the influence of 14-3-3ζ causing metastatic cancer through the interaction of YAP1 and β-TRCP

Abstract

14-3-3ζ acts as molecular switch in regulating TGF-β pathway, which turns from tumor suppressor in early stage of breast cancer to metastatic promoter in late stage. Such drift is due to binding of 14-3-3ζ with YAP1 and β-TRCP in premalignant and cancer cells respectively. Due to such condemnatory role of 14-3-3ζ involved in cancer and metastasis, we predicted Gln15, Glu17, Tyr211, Gln219 as hotspot residues of 14-3-3ζ during interaction with YAP1 protein. Similarly, we identified Gln15, Tyr211, Leu216, Leu220 as hotspot residues of 14-3-3ζ during interaction with β-TRCP protein. Targeting these residues of 14-3-3ζ can block cancer and metastasis caused by malfunction of TGF-β pathway. In this work, we also predicted YAP1 as Intrinsically disordered protein (IDP) and such protein binds with other protein manifest either induced fit mechanism or conformational selection. Intuitively, we found 14-3-3ζ has high affinity towards phosphorylated YAP1 at Ser127 rather than unphosphorylated YAP1 which is very well concede with previously reported experimental works. Thus we performed molecular dynamics simulation analysis to reveal the conformational changes of YAP1 beyond phosphorylation in atomistic level. Our work clearly pictures the impact of phosphorylation on YAP1 in conformational changes and regulating its function.

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Publication details

The article was received on 09 May 2017, accepted on 10 Jul 2017 and first published on 10 Jul 2017


Article type: Paper
DOI: 10.1039/C7MB00271H
Citation: Mol. BioSyst., 2017, Accepted Manuscript
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    Expediting dynamics approach to understand the influence of 14-3-3ζ causing metastatic cancer through the interaction of YAP1 and β-TRCP

    K. D, S. Ramireddy, R. P and S. C, Mol. BioSyst., 2017, Accepted Manuscript , DOI: 10.1039/C7MB00271H

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