Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays.
Identifieur interne : 001E67 ( Main/Exploration ); précédent : 001E66; suivant : 001E68Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays.
Auteurs : Avinash Persaud [Canada] ; Philipp Alberts ; Eva M. Amsen ; Xuejian Xiong ; James Wasmuth ; Zachary Saadon ; Chris Fladd ; John Parkinson ; Daniela RotinSource :
- Molecular systems biology [ 1744-4292 ] ; 2009.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Endosomal Sorting Complexes Required for Transport, Ubiquitin-Protein Ligases.
- Humans, Protein Array Analysis, Protein Binding, Proteome, Substrate Specificity.
Abstract
Target recognition by the ubiquitin system is mediated by E3 ubiquitin ligases. Nedd4 family members are E3 ligases comprised of a C2 domain, 2-4 WW domains that bind PY motifs (L/PPxY) and a ubiquitin ligase HECT domain. The nine Nedd4 family proteins in mammals include two close relatives: Nedd4 (Nedd4-1) and Nedd4L (Nedd4-2), but their global substrate recognition or differences in substrate specificity are unknown. We performed in vitro ubiquitylation and binding assays of human Nedd4-1 and Nedd4-2, and rat-Nedd4-1, using protein microarrays spotted with approximately 8200 human proteins. Top hits (substrates) for the ubiquitylation and binding assays mostly contain PY motifs. Although several substrates were recognized by both Nedd4-1 and Nedd4-2, others were specific to only one, with several Tyr kinases preferred by Nedd4-1 and some ion channels by Nedd4-2; this was subsequently validated in vivo. Accordingly, Nedd4-1 knockdown or knockout in cells led to sustained signalling via some of its substrate Tyr kinases (e.g. FGFR), suggesting Nedd4-1 suppresses their signalling. These results demonstrate the feasibility of identifying substrates and deciphering substrate specificity of mammalian E3 ligases.
DOI: 10.1038/msb.2009.85
PubMed: 19953087
Affiliations:
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Amsen</name></author><author><name sortKey="Xiong, Xuejian" sort="Xiong, Xuejian" uniqKey="Xiong X" first="Xuejian" last="Xiong">Xuejian Xiong</name></author><author><name sortKey="Wasmuth, James" sort="Wasmuth, James" uniqKey="Wasmuth J" first="James" last="Wasmuth">James Wasmuth</name></author><author><name sortKey="Saadon, Zachary" sort="Saadon, Zachary" uniqKey="Saadon Z" first="Zachary" last="Saadon">Zachary Saadon</name></author><author><name sortKey="Fladd, Chris" sort="Fladd, Chris" uniqKey="Fladd C" first="Chris" last="Fladd">Chris Fladd</name></author><author><name sortKey="Parkinson, John" sort="Parkinson, John" uniqKey="Parkinson J" first="John" last="Parkinson">John Parkinson</name></author><author><name sortKey="Rotin, Daniela" sort="Rotin, Daniela" uniqKey="Rotin D" first="Daniela" last="Rotin">Daniela Rotin</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2009">2009</date><idno type="RBID">pubmed:19953087</idno><idno type="pmid">19953087</idno><idno type="doi">10.1038/msb.2009.85</idno><idno type="wicri:Area/PubMed/Corpus">000F21</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000F21</idno><idno type="wicri:Area/PubMed/Curation">000F21</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000F21</idno><idno type="wicri:Area/PubMed/Checkpoint">000F21</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000F21</idno><idno type="wicri:Area/Ncbi/Merge">000B82</idno><idno type="wicri:Area/Ncbi/Curation">000B82</idno><idno type="wicri:Area/Ncbi/Checkpoint">000B82</idno><idno type="wicri:Area/Main/Merge">002020</idno><idno type="wicri:Area/Main/Curation">001E67</idno><idno type="wicri:Area/Main/Exploration">001E67</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays.</title><author><name sortKey="Persaud, Avinash" sort="Persaud, Avinash" uniqKey="Persaud A" first="Avinash" last="Persaud">Avinash Persaud</name><affiliation wicri:level="1"><nlm:affiliation>Programs in Cell Biology and Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Programs in Cell Biology and Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Alberts, Philipp" sort="Alberts, Philipp" uniqKey="Alberts P" first="Philipp" last="Alberts">Philipp Alberts</name></author><author><name sortKey="Amsen, Eva M" sort="Amsen, Eva M" uniqKey="Amsen E" first="Eva M" last="Amsen">Eva M. Amsen</name></author><author><name sortKey="Xiong, Xuejian" sort="Xiong, Xuejian" uniqKey="Xiong X" first="Xuejian" last="Xiong">Xuejian Xiong</name></author><author><name sortKey="Wasmuth, James" sort="Wasmuth, James" uniqKey="Wasmuth J" first="James" last="Wasmuth">James Wasmuth</name></author><author><name sortKey="Saadon, Zachary" sort="Saadon, Zachary" uniqKey="Saadon Z" first="Zachary" last="Saadon">Zachary Saadon</name></author><author><name sortKey="Fladd, Chris" sort="Fladd, Chris" uniqKey="Fladd C" first="Chris" last="Fladd">Chris Fladd</name></author><author><name sortKey="Parkinson, John" sort="Parkinson, John" uniqKey="Parkinson J" first="John" last="Parkinson">John Parkinson</name></author><author><name sortKey="Rotin, Daniela" sort="Rotin, Daniela" uniqKey="Rotin D" first="Daniela" last="Rotin">Daniela Rotin</name></author></analytic><series><title level="j">Molecular systems biology</title><idno type="eISSN">1744-4292</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Endosomal Sorting Complexes Required for Transport (metabolism)</term><term>Humans</term><term>Protein Array Analysis</term><term>Protein Binding</term><term>Proteome</term><term>Substrate Specificity</term><term>Ubiquitin-Protein Ligases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Endosomal Sorting Complexes Required for Transport</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Protein Array Analysis</term><term>Protein Binding</term><term>Proteome</term><term>Substrate Specificity</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Target recognition by the ubiquitin system is mediated by E3 ubiquitin ligases. Nedd4 family members are E3 ligases comprised of a C2 domain, 2-4 WW domains that bind PY motifs (L/PPxY) and a ubiquitin ligase HECT domain. The nine Nedd4 family proteins in mammals include two close relatives: Nedd4 (Nedd4-1) and Nedd4L (Nedd4-2), but their global substrate recognition or differences in substrate specificity are unknown. We performed in vitro ubiquitylation and binding assays of human Nedd4-1 and Nedd4-2, and rat-Nedd4-1, using protein microarrays spotted with approximately 8200 human proteins. Top hits (substrates) for the ubiquitylation and binding assays mostly contain PY motifs. Although several substrates were recognized by both Nedd4-1 and Nedd4-2, others were specific to only one, with several Tyr kinases preferred by Nedd4-1 and some ion channels by Nedd4-2; this was subsequently validated in vivo. Accordingly, Nedd4-1 knockdown or knockout in cells led to sustained signalling via some of its substrate Tyr kinases (e.g. FGFR), suggesting Nedd4-1 suppresses their signalling. These results demonstrate the feasibility of identifying substrates and deciphering substrate specificity of mammalian E3 ligases.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Alberts, Philipp" sort="Alberts, Philipp" uniqKey="Alberts P" first="Philipp" last="Alberts">Philipp Alberts</name><name sortKey="Amsen, Eva M" sort="Amsen, Eva M" uniqKey="Amsen E" first="Eva M" last="Amsen">Eva M. Amsen</name><name sortKey="Fladd, Chris" sort="Fladd, Chris" uniqKey="Fladd C" first="Chris" last="Fladd">Chris Fladd</name><name sortKey="Parkinson, John" sort="Parkinson, John" uniqKey="Parkinson J" first="John" last="Parkinson">John Parkinson</name><name sortKey="Rotin, Daniela" sort="Rotin, Daniela" uniqKey="Rotin D" first="Daniela" last="Rotin">Daniela Rotin</name><name sortKey="Saadon, Zachary" sort="Saadon, Zachary" uniqKey="Saadon Z" first="Zachary" last="Saadon">Zachary Saadon</name><name sortKey="Wasmuth, James" sort="Wasmuth, James" uniqKey="Wasmuth J" first="James" last="Wasmuth">James Wasmuth</name><name sortKey="Xiong, Xuejian" sort="Xiong, Xuejian" uniqKey="Xiong X" first="Xuejian" last="Xiong">Xuejian Xiong</name></noCountry><country name="Canada"><noRegion><name sortKey="Persaud, Avinash" sort="Persaud, Avinash" uniqKey="Persaud A" first="Avinash" last="Persaud">Avinash Persaud</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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