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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Format: | Article |
Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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Series: | PLoS ONE |
Online Access: | https://doi.org/10.1371/journal.pone.0258315 |
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author | A Katherine Hatstat Michael D Pupi Dewey G McCafferty |
author_facet | A Katherine Hatstat Michael D Pupi Dewey G McCafferty |
author_sort | A Katherine Hatstat |
collection | DOAJ |
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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institution | Directory Open Access Journal |
issn | 1932-6203 |
language | English |
last_indexed | 2024-04-13T11:11:42Z |
publishDate | 2021-01-01 |
publisher | Public Library of Science (PLoS) |
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series | PLoS ONE |
spelling | doaj.art-fe4dfcb0bce545759a11255ebe61711e2022-12-22T02:49:06ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-011610e025831510.1371/journal.pone.0258315Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases.A Katherine HatstatMichael D PupiDewey G McCaffertyThe 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.https://doi.org/10.1371/journal.pone.0258315 |
spellingShingle | A Katherine Hatstat Michael D Pupi Dewey G McCafferty Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases. PLoS ONE |
title | Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases. |
title_full | Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases. |
title_fullStr | Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases. |
title_full_unstemmed | Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases. |
title_short | Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases. |
title_sort | predicting py motif mediated protein protein interactions in the nedd4 family of ubiquitin ligases |
url | https://doi.org/10.1371/journal.pone.0258315 |
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