5CQ2

Crystal Structure of tandem WW domains of ITCH in complex with TXNIP peptide

「4ROH」から置き換えられました

5CQ2 の概要

• エントリーDOI: 10.2210/pdb5cq2/pdb
• 分子名称: E3 ubiquitin-protein ligase Itchy homolog, Thioredoxin-interacting protein, UNKNOWN ATOM OR ION, ... (4 entities in total)
• 機能のキーワード: structural genomics, structural genomics consortium, sgc, ligase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane: Q96J02; Cytoplasm : Q9H3M7
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 13131.59

構造登録者

Liu, Y.,Tempel, W.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Min, J.,Structural Genomics Consortium (SGC) (登録日: 2015-07-21, 公開日: 2015-09-16, 最終更新日: 2024-11-20)

主引用文献

Liu, Y.,Lau, J.,Li, W.,Tempel, W.,Li, L.,Dong, A.,Narula, A.,Qin, S.,Min, J.
Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP.
Biochem.J., 473:179-187, 2016

PubMed 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 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).

PubMed: 26527736
DOI: 10.1042/BJ20150830

実験手法

X-RAY DIFFRACTION (1.4 Å)