Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases.
The Nedd4 family contains several structurally related but functionally distinct HECT-type ubiquitin ligases. The members of the Nedd4 family are known to recognize substrates through their multiple WW domains, which recognize PY motifs (PPxY, LPxY) or phospho-threonine or phospho-serine residues. To better understand protein interactor recognition mechanisms across the Nedd4 family, we report the development and implementation of a python-based tool, PxYFinder, to identify PY motifs in the primary sequences of previously identified interactors of Nedd4 and related ligases. Using PxYFinder, we find that, on average, half of Nedd4 family interactions are likely PY-motif mediated. Further, we find that PPxY motifs are more prevalent than LPxY motifs and are more likely to occur in proline-rich regions and that PPxY regions are more disordered on average relative to LPxY-containing regions. Informed by consensus sequences for PY motifs across the Nedd4 interactome, we rationally designed a focused peptide library and employed a computational screen, revealing sequence- and biomolecular interaction-dependent determinants of WW-domain/PY-motif interactions. Cumulatively, our efforts provide a new bioinformatic tool and expand our understanding of sequence and structural factors that contribute to PY-motif mediated interactor recognition across the Nedd4 family.
Duke Scholars
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Related Subject Headings
- Ubiquitination
- Solvents
- Protein Interaction Mapping
- Protein Binding
- Peptide Library
- Nedd4 Ubiquitin Protein Ligases
- Molecular Sequence Annotation
- Molecular Docking Simulation
- General Science & Technology
- Gene Ontology
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Ubiquitination
- Solvents
- Protein Interaction Mapping
- Protein Binding
- Peptide Library
- Nedd4 Ubiquitin Protein Ligases
- Molecular Sequence Annotation
- Molecular Docking Simulation
- General Science & Technology
- Gene Ontology