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Biochimie. 2014 Jun;101:192-202. doi: 10.1016/j.biochi.2014.01.011. Epub 2014 Jan 25.

Molecular basis of the binding of YAP transcriptional regulator to the ErbB4 receptor tyrosine kinase.

Author information

1
Department of Biochemistry & Molecular Biology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
2
Weis Center for Research, Geisinger Clinic, Danville, PA 17822, USA; Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
3
Department of Biochemistry & Molecular Biology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Electronic address: amjad@farooqlab.net.

Abstract

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.

KEYWORDS:

Conformational dynamics; PPXY motifs; Structural analysis; WW-ligand thermodynamics

PMID:
24472438
PMCID:
PMC3995836
DOI:
10.1016/j.biochi.2014.01.011
[Indexed for MEDLINE]
Free PMC Article

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