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- Title
Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP.
- Authors
Yanli Liu; Lau, Johnathan; Weiguo Li; Tempel, Wolfram; Li Li; Aiping Dong; Narula, Ashrut; Su Qin; Jinrong Min
- Abstract
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 fourWWdomains of Itch with the two PPxYmotifs 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 fourWWdomains 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).
- Subjects
THIOREDOXIN-interacting protein; PROTEIN structure; CELLULAR control mechanisms; ANTIOXIDANTS; CELLULAR signal transduction
- Publication
Biochemical Journal, 2016, Vol 473, Issue 2, p179
- ISSN
0264-6021
- Publication type
Article
- DOI
10.1042/BJ20150830