Journal
BIOCHIMIE
Volume 101, Issue -, Pages 192-202Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2014.01.011
Keywords
WW-ligand thermodynamics; PPXY motifs; Structural analysis; Conformational dynamics
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Funding
- National Institutes of Health [R01-GM083897, T32-CA119929]
- USylvester Braman Family Breast Cancer Institute
- Department of Health of Pennsylvania [RFA 50709, RFA 60707]
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The newly discovered transactivation function of ErbB4 receptor tyrosine kinase is believed to be mediated by virtue of the ability of its proteolytically-cleaved intracellular domain (ICD) to physically associate with YAP2 transcriptional regulator. In an effort to unearth the molecular basis of YAP2 ErbB4 interaction, we have conducted a detailed biophysical analysis of the binding of WW domains of YAP2 to PPXY motifs located within the ICD of ErbB4. Our data show that the WW1 domain of YAP2 binds to PPXY motifs within the ICD in a differential manner and that this behavior is by and large replicated by the WW2 domain. Remarkably, while both WW domains absolutely require the integrity of the PPXY consensus sequence, non-consensus residues within and flanking this motif do not appear to be critical for binding. In spite of this shared mode of binding, the WW domains of YAP2 display distinct conformational dynamics in complex with PPXY motifs derived from ErbB4. Collectively, our study lends new insights into the molecular basis of a key protein protein interaction involved in a diverse array of cellular processes. (C) 2014 Elsevier Masson SAS. All rights reserved.
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