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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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 ; Pupi, Michael D ; McCafferty, Dewey G</creator><contributor>Nanda, Vikas</contributor><creatorcontrib>Hatstat, A. Katherine ; Pupi, Michael D ; McCafferty, Dewey G ; Nanda, Vikas</creatorcontrib><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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0258315</identifier><identifier>PMID: 34637467</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>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</subject><ispartof>PloS one, 2021-10, Vol.16 (10), p.e0258315-e0258315</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Hatstat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Hatstat et al 2021 Hatstat et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c669t-323cf128d4321583c75b0e70f57eba8137c55b3a2b6cae51633557201ed2cd563</citedby><cites>FETCH-LOGICAL-c669t-323cf128d4321583c75b0e70f57eba8137c55b3a2b6cae51633557201ed2cd563</cites><orcidid>0000-0002-3253-9233</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509885/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509885/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids></links><search><contributor>Nanda, Vikas</contributor><creatorcontrib>Hatstat, A. Katherine</creatorcontrib><creatorcontrib>Pupi, Michael D</creatorcontrib><creatorcontrib>McCafferty, Dewey G</creatorcontrib><title>Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases</title><title>PloS one</title><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.</description><subject>Analysis</subject><subject>Annotations</subject><subject>Biology and Life Sciences</subject><subject>Computer applications</subject><subject>Datasets</subject><subject>Domains</subject><subject>Enzymes</subject><subject>Health aspects</subject><subject>Identification and classification</subject><subject>Ligases</subject><subject>Localization</subject><subject>Observations</subject><subject>Ontology</subject><subject>Peptides</subject><subject>Proline</subject><subject>Protein interaction</subject><subject>Protein-protein interactions</subject><subject>Proteins</subject><subject>Recognition</subject><subject>Research and Analysis Methods</subject><subject>Substrates</subject><subject>Threonine</subject><subject>Trends</subject><subject>Ubiquitin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6DwQLguhFx3w0SXuzsCx-DCzu4hd4FdL0pJOhbWaTVNx_b2anylb2QnKR5OTJe3JecrLsOUYrTAV-u3WTH1W_2rkRVoiwimL2IDvGNSUFJ4g-vLM-yp6EsEWI0Yrzx9kRLTkVJRfHWXPlobU62rHLr37kg4vWFEMKqQhtvvMugh2Lec7tGMGrRLsxpE0eN5B_grYtc6MG29_kzuRTY68nmwTz3nYqQHiaPTKqD_Bsnk-yb-_ffT3_WFxcflifn10UmvM6FpRQbTCp2pISnKrRgjUIBDJMQKOqVLNmrKGKNFwrYJhTypggCENLdMs4PcleHHR3vQtytifI5AwmlJUlTsT6QLRObeXO20H5G-mUlbcB5zupfLS6B2mgbI1uUKOBlUywWmFMGIMGOBYYQ9I6nbNNTfJLwxi96heiy5PRbmTnfsqKobqqWBJ4PQt4dz1BiHKwQUPfqxHcdHh3RUpWk4S-_Ae9v7qZ6lQqwI7Gpbx6LyrPuKiEEBXep13dQ6XRwmB1-kvGpvjiwpvFhcRE-BU7NYUg118-_z97-X3JvrrDbkD1cRNcP91-riVYHkDtXQgezF-TMZL7Vvjjhty3gpxbgf4GOw35_A</recordid><startdate>20211012</startdate><enddate>20211012</enddate><creator>Hatstat, A. 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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. 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.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>34637467</pmid><doi>10.1371/journal.pone.0258315</doi><tpages>e0258315</tpages><orcidid>https://orcid.org/0000-0002-3253-9233</orcidid><oa>free_for_read</oa></addata></record> |
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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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