TXNIP (thioredoxin-interacting protein) negatively regulates the antioxidative activity of thioredoxin and participates in pleiotropic cellular processes. Its deregulation is linked to various human diseases, including diabetes, acute myeloid leukaemia and cardiovascular diseases. The E3 ubiquitin ligase Itch (Itchy homologue) polyubiquitinates TXNIP to promote its degradation via the ubiquitin–proteasome pathway, and this Itch-mediated polyubiquitination of TXNIP is dependent on the interaction of the four WW domains of Itch with the two PPxY motifs of TXNIP. However, the molecular mechanism of this interaction of TXNIP with Itch remains elusive. In the present study, we found that each of the four WW domains of Itch exhibited different binding affinities for TXNIP, whereas multivalent engagement between the four WW domains of Itch and the two PPxY motifs of TXNIP resulted in their strong binding avidity. Our structural analyses demonstrated that the third and fourth WW domains of Itch were able to recognize both PPxY motifs of TXNIP simultaneously, supporting a multivalent binding mode between Itch and TXNIP. Interestingly, the phosphorylation status on the tyrosine residue of the PPxY motifs of TXNIP serves as a molecular switch in its choice of binding partners and thereby downstream biological signalling outcomes. Phosphorylation of this tyrosine residue of TXNIP diminished the binding capability of PPxY motifs of TXNIP to Itch, whereas this phosphorylation is a prerequisite to the binding activity of TXNIP to SHP2 [SH2 (Src homology 2) domain-containing protein tyrosine phosphatase 2] and their roles in stabilizing the phosphorylation and activation of CSK (c-Src tyrosine kinase).
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Research Article|
January 05 2016
Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP
Yanli Liu;
Yanli Liu
1
*Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Central China Normal University, Wuhan 430079, P.R. China
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
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Johnathan Lau;
Johnathan Lau
1
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
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Weiguo Li;
Weiguo Li
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
‡Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Central China Normal University, Wuhan 430079, P.R. China
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Wolfram Tempel;
Wolfram Tempel
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
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Li Li;
Li Li
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
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Aiping Dong;
Aiping Dong
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
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Ashrut Narula;
Ashrut Narula
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
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Su Qin;
Su Qin
2
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
§Materials Characterization and Preparation Center and Life Science Research Center, South University of Science and Technology of China, Shenzhen 518055, China
2Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Jinrong Min
Jinrong Min
2
*Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Central China Normal University, Wuhan 430079, P.R. China
†Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada, M5G 1L7
║Department of Physiology, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
2Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Publisher: Portland Press Ltd
Received:
July 24 2015
Revision Received:
October 30 2015
Accepted:
November 02 2015
Accepted Manuscript online:
November 02 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 Authors; published by Portland Press Limited
2016
Biochem J (2016) 473 (2): 179–187.
Article history
Received:
July 24 2015
Revision Received:
October 30 2015
Accepted:
November 02 2015
Accepted Manuscript online:
November 02 2015
Citation
Yanli Liu, Johnathan Lau, Weiguo Li, Wolfram Tempel, Li Li, Aiping Dong, Ashrut Narula, Su Qin, Jinrong Min; Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP. Biochem J 15 January 2016; 473 (2): 179–187. doi: https://doi.org/10.1042/BJ20150830
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