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. T...

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Veröffentlicht in:PloS one 2021-10, Vol.16 (10), p.e0258315-e0258315
Hauptverfasser: Hatstat, A. Katherine, Pupi, Michael D, McCafferty, Dewey G
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Pupi, Michael D
McCafferty, Dewey G
description 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.
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Katherine</au><au>Pupi, Michael D</au><au>McCafferty, Dewey G</au><au>Nanda, Vikas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases</atitle><jtitle>PloS one</jtitle><date>2021-10-12</date><risdate>2021</risdate><volume>16</volume><issue>10</issue><spage>e0258315</spage><epage>e0258315</epage><pages>e0258315-e0258315</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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. 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subjects Analysis
Annotations
Biology and Life Sciences
Computer applications
Datasets
Domains
Enzymes
Health aspects
Identification and classification
Ligases
Localization
Observations
Ontology
Peptides
Proline
Protein interaction
Protein-protein interactions
Proteins
Recognition
Research and Analysis Methods
Substrates
Threonine
Trends
Ubiquitin
title Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases
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