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PDBsum entry 5cq2
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References listed in PDB file
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Key reference
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Title
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Structural basis for the regulatory role of the ppxy motifs in the thioredoxin-Interacting protein txnip.
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Authors
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Y.Liu,
J.Lau,
W.Li,
W.Tempel,
L.Li,
A.Dong,
A.Narula,
S.Qin,
J.Min.
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Ref.
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Biochem J, 2016,
473,
179-187.
[DOI no: ]
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PubMed id
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Abstract
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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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