Biophysical basis of the binding of WWOX tumor suppressor to WBP1 and WBP2 adaptors

Caleb B. McDonald, Laura Buffa, Tomer Bar-Mag, Zaidoun Salah, Vikas Bhat, David C. Mikles, Brian J. Deegan, Kenneth L. Seldeen, Arun Malhotra, Marius Sudol, Rami I. Aqeilan, Zafar Nawaz, Amjad Farooq

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


The WW-containing oxidoreductase (WWOX) tumor suppressor participates in a diverse array of cellular activities by virtue of its ability to recognize WW-binding protein 1 (WBP1) and WW-binding protein 2 (WBP2) signaling adaptors among a wide variety of other ligands. Herein, using a multitude of biophysical techniques, we provide evidence that while the WW1 domain of WWOX binds to PPXY motifs within WBP1 and WBP2 in a physiologically relevant manner, the WW2 domain exhibits no affinity toward any of these PPXY motifs. Importantly, our data suggest that while R25/W44 residues located within the binding pocket of a triple-stranded β-fold of WW1 domain are critical for the recognition of PPXY ligands, they are replaced by the chemically distinct E66/Y85 duo at structurally equivalent positions within the WW2 domain, thereby accounting for its failure to bind PPXY ligands. Predictably, not only does the introduction of E66R/Y85W double substitution within the WW2 domain result in gain of function but the resulting engineered domain, hereinafter referred to as WW2-RW, also appears to be a much stronger binding partner of WBP1 and WBP2 than the wild-type WW1 domain. We also show that while the WW1 domain is structurally disordered and folds upon ligand binding, the WW2 domain not only adopts a fully structured conformation but also aids stabilization and ligand binding to WW1 domain. This salient observation implies that the WW2 domain likely serves as a chaperone to augment the physiological function of WW1 domain within WWOX. Collectively, our study lays the groundwork for understanding the molecular basis of a key protein-protein interaction pertinent to human health and disease.

Original languageEnglish (US)
Pages (from-to)58-74
Number of pages17
JournalJournal of molecular biology
Issue number1
StatePublished - Sep 7 2012


  • WW domain chaperone
  • WW domain engineering
  • WW tandem domains
  • WW-ligand thermodynamics

ASJC Scopus subject areas

  • Molecular Biology


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