Structural basis and targeting of the interaction between fibroblast growth factor-inducible 14 and tumor necrosis factor-like weak inducer of apoptosis

Harshil Dhruv, Joseph C. Loftus, Pooja Narang, Joachim L. Petit, Maureen Fameree, Julien Burton, Giresse Tchegho, Donald Chow, Holly Yin, Yousef Al-Abed, Michael E. Berens, Nhan L. Tran, Nathalie Meurice

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Deregulation of the TNF-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling pathway is observed in many diseases, including inflammation, autoimmune diseases, and cancer. Activation of Fn14 signaling by TWEAK binding triggers cell invasion and survival and therefore represents an attractive pathway for therapeutic intervention. Based on structural studies of the TWEAK-binding cysteine-rich domain of Fn14, several homology models of TWEAK were built to investigate plausible modes of TWEAKFn14 interaction. Two promising models, centered on different anchoring residues of TWEAK (tyrosine 176 and tryptophan 231), were prioritized using a data-driven strategy. Site-directed mutagenesis ofTWEAKat Tyr176, but not Trp231, resulted in the loss of TWEAK binding to Fn14 substantiating Tyr176 as the anchoring residue. Importantly, mutation of TWEAK at Tyr176 did not disruptTWEAKtrimerization but failed to induce Fn14- mediated nuclear factor κ-light chain enhancer of activated B cell (NF-κB) signaling. The validated structural models were utilized in a virtual screen to design a targeted library of small molecules predicted to disrupt the TWEAK-Fn14 interaction. 129 small molecules were screened iteratively, with identification of molecules producing up to 37% inhibition of TWEAKFn14 binding. In summary, we present a data-driven in silico study revealing key structural elements of the TWEAK-Fn14 interaction, followed by experimental validation, serving as a guide for the design of small molecule inhibitors of theTWEAKFn14 ligand-receptor interaction. Our results validate the TWEAK-Fn14 interaction as a chemically tractable target and provide the foundation for further exploration utilizing chemical biology approaches focusing on validating this system as a therapeutic target in invasive cancers.

Original languageEnglish (US)
Pages (from-to)32261-32276
Number of pages16
JournalJournal of Biological Chemistry
Volume288
Issue number45
DOIs
StatePublished - Nov 8 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Dhruv, H., Loftus, J. C., Narang, P., Petit, J. L., Fameree, M., Burton, J., Tchegho, G., Chow, D., Yin, H., Al-Abed, Y., Berens, M. E., Tran, N. L., & Meurice, N. (2013). Structural basis and targeting of the interaction between fibroblast growth factor-inducible 14 and tumor necrosis factor-like weak inducer of apoptosis. Journal of Biological Chemistry, 288(45), 32261-32276. https://doi.org/10.1074/jbc.M113.493536