Molecular origin of the binding of WWOX tumor suppressor to erbb4 receptor tyrosine kinase

Brett J. Schuchardt, Vikas Bhat, David C. Mikles, Caleb B. McDonald, Marius Sudol, Amjad Farooq

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The ability of WWOX tumor suppressor to physically associate with the intracellular domain (ICD) of ErbB4 receptor tyrosine kinase is believed to play a central role in downregulating the transcriptional function of the latter. Herein, using various biophysical methods, we show that while the WW1 domain of WWOX binds to PPXY motifs located within the ICD of ErbB4 in a physiologically relevant manner, the WW2 domain does not. Importantly, while the WW1 domain absolutely requires the integrity of the PPXY consensus sequence, nonconsensus residues within and flanking this motif do not appear to be critical for binding. This strongly suggests that the WW1 domain of WWOX is rather promiscuous toward its cellular partners. We also provide evidence that the lack of binding of the WW2 domain of WWOX to PPXY motifs is due to the replacement of a signature tryptophan, lining the hydrophobic ligand binding groove, with tyrosine (Y85). Consistent with this notion, the Y85W substitution within the WW2 domain exquisitely restores its binding to PPXY motifs in a manner akin to the binding of the WW1 domain of WWOX. Of particular significance is the observation that the WW2 domain augments the binding of the WW1 domain to ErbB4, implying that the former serves as a chaperone within the context of the WW1-WW2 tandem module of WWOX in agreement with our findings reported previously. Altogether, our study sheds new light on the molecular basis of an important WW-ligand interaction involved in mediating a plethora of cellular processes.

Original languageEnglish
Pages (from-to)9223-9236
Number of pages14
JournalBiochemistry
Volume52
Issue number51
DOIs
StatePublished - Dec 23 2013

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Receptor Protein-Tyrosine Kinases
Tumors
Ligands
Consensus Sequence
Linings
Tryptophan
Tyrosine
Neoplasms
Substitution reactions
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Schuchardt, B. J., Bhat, V., Mikles, D. C., McDonald, C. B., Sudol, M., & Farooq, A. (2013). Molecular origin of the binding of WWOX tumor suppressor to erbb4 receptor tyrosine kinase. Biochemistry, 52(51), 9223-9236. https://doi.org/10.1021/bi400987k

Molecular origin of the binding of WWOX tumor suppressor to erbb4 receptor tyrosine kinase. / Schuchardt, Brett J.; Bhat, Vikas; Mikles, David C.; McDonald, Caleb B.; Sudol, Marius; Farooq, Amjad.

In: Biochemistry, Vol. 52, No. 51, 23.12.2013, p. 9223-9236.

Research output: Contribution to journalArticle

Schuchardt, BJ, Bhat, V, Mikles, DC, McDonald, CB, Sudol, M & Farooq, A 2013, 'Molecular origin of the binding of WWOX tumor suppressor to erbb4 receptor tyrosine kinase', Biochemistry, vol. 52, no. 51, pp. 9223-9236. https://doi.org/10.1021/bi400987k
Schuchardt, Brett J. ; Bhat, Vikas ; Mikles, David C. ; McDonald, Caleb B. ; Sudol, Marius ; Farooq, Amjad. / Molecular origin of the binding of WWOX tumor suppressor to erbb4 receptor tyrosine kinase. In: Biochemistry. 2013 ; Vol. 52, No. 51. pp. 9223-9236.
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