Smad7 Binds Differently to Individual and Tandem WW3 and WW4 Domains of WWP2 Ubiquitin Ligase Isoforms
Wahl L. C., Watt J. E., Yim H. T. T., De B. D., Tolchard J., Sund S. M., Blumenschein T. M. A., Chantry A.
International Journal of Molecular Sciences
Vol.20, Issue19, Num.4682
Опубликовано: 2019
Тип ресурса: Статья
Аннотация:
WWP2 is an E3 ubiquitin ligase that differentially regulates the contextual tumour suppressor/progressor TGFβ signalling pathway by alternate isoform expression. WWP2 isoforms select signal transducer Smad2/3 or inhibitor Smad7 substrates for degradation through different compositions of protein-protein interactionWWdomains. The WW4 domain-containing WWP2-C induces Smad7 turnover in vivo and positively regulates the metastatic epithelial-mesenchymal transition programme. This activity and the overexpression of these isoforms in human cancers make them candidates for therapeutic intervention. Here, we use NMR spectroscopy to solve the solution structure of the WWP2 WW4 domain and observe the binding characteristics of Smad7 substrate peptide. We also reveal that WW4 has an enhanced affinity for a Smad7 peptide phosphorylated at serine 206 adjacent to the PPxY motif. Using the same approach, we show that the WW3 domain also binds Smad7 and has significantly enhanced Smad7 binding affinit
Ключевые слова:
E3 ubiquitin ligase; NEDD4; Protein interaction; Smad; Smad7; TGFβ signalling; Transforming growth factor beta; WW domain
isoenzyme; Smad7 protein; ubiquitin protein ligase E3; unclassified drug; wwp 2 ubiquitin ligase; isoenzyme; Smad7 protein; SMAD7 protein, human; transforming growth factor beta; ubiquitin protein ligase; WWP2 protein, human; animal cell; Article; binding affinity; enzyme structure; human; human cell; mouse; nonhuman; nuclear magnetic resonance spectroscopy; protein binding; protein domain; protein expression; protein interaction; protein phosphorylation; protein protein interaction; protein ww 3 domain; protein ww 4 domain; TGF beta signaling; chemistry; genetics; HEK293 cell line; metabolism; molecular model; signal transduction; WW domain; HEK293 Cells; Humans; Isoenzymes; Magnetic Resonance Spectroscopy; Models, Molecular; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta; Ubiquitin-Protein Ligases; WW Domains
Язык текста: Английский
ISSN: 1661-6596
Wahl L. C.
Watt J. E.
Yim H. T. T.
De B. D. Bourcier D.
Tolchard J.
Sund S. M. Surinder Mokhan 1969-
Blumenschein T. M. A.
Chantry A.
Wахл Л. C.
Wатт Й. Е.
Yим Х. Т. Т.
Де Б. Д. Боурcиер Д.
Толчард Й.
Сунд С. М. Суриндер Мохан 1969-
Блуменсчеин Т. М. А.
Чантрy А.
Smad7 Binds Differently to Individual and Tandem WW3 and WW4 Domains of WWP2 Ubiquitin Ligase Isoforms
Текст визуальный непосредственный
International Journal of Molecular Sciences
Vol.20, Issue19 Num.4682
2019
Статья
E3 ubiquitin ligase NEDD4 Protein interaction Smad Smad7 TGFβ signalling Transforming growth factor beta WW domain
isoenzyme Smad7 protein ubiquitin protein ligase E3 unclassified drug wwp 2 ubiquitin ligase isoenzyme Smad7 protein SMAD7 protein, human transforming growth factor beta ubiquitin protein ligase WWP2 protein, human animal cell Article binding affinity enzyme structure human human cell mouse nonhuman nuclear magnetic resonance spectroscopy protein binding protein domain protein expression protein interaction protein phosphorylation protein protein interaction protein ww 3 domain protein ww 4 domain TGF beta signaling chemistry genetics HEK293 cell line metabolism molecular model signal transduction WW domain HEK293 Cells Humans Isoenzymes Magnetic Resonance Spectroscopy Models, Molecular Signal Transduction Smad7 Protein Transforming Growth Factor beta Ubiquitin-Protein Ligases WW Domains
WWP2 is an E3 ubiquitin ligase that differentially regulates the contextual tumour suppressor/progressor TGFβ signalling pathway by alternate isoform expression. WWP2 isoforms select signal transducer Smad2/3 or inhibitor Smad7 substrates for degradation through different compositions of protein-protein interactionWWdomains. The WW4 domain-containing WWP2-C induces Smad7 turnover in vivo and positively regulates the metastatic epithelial-mesenchymal transition programme. This activity and the overexpression of these isoforms in human cancers make them candidates for therapeutic intervention. Here, we use NMR spectroscopy to solve the solution structure of the WWP2 WW4 domain and observe the binding characteristics of Smad7 substrate peptide. We also reveal that WW4 has an enhanced affinity for a Smad7 peptide phosphorylated at serine 206 adjacent to the PPxY motif. Using the same approach, we show that the WW3 domain also binds Smad7 and has significantly enhanced Smad7 binding affinit