5DF6

Crystal structure of PTPN11 tandem SH2 domains in complex with a TXNIP peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


This is version 1.7 of the entry. See complete history


Literature

Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP.

Liu, Y.Lau, J.Li, W.Tempel, W.Li, L.Dong, A.Narula, A.Qin, S.Min, J.

(2016) Biochem J 473: 179-187

  • DOI: https://doi.org/10.1042/BJ20150830
  • Primary Citation of Related Structures:  
    5CQ2, 5DF6

  • 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).


  • Organizational Affiliation

    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.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein phosphatase non-receptor type 11255Homo sapiensMutation(s): 0 
Gene Names: PTPN11PTP2CSHPTP2
EC: 3.1.3.48
UniProt & NIH Common Fund Data Resources
Find proteins for Q06124 (Homo sapiens)
Explore Q06124 
Go to UniProtKB:  Q06124
PHAROS:  Q06124
GTEx:  ENSG00000179295 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ06124
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
txnip
B, C
13Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H3M7 (Homo sapiens)
Explore Q9H3M7 
Go to UniProtKB:  Q9H3M7
PHAROS:  Q9H3M7
GTEx:  ENSG00000265972 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H3M7
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 28.47α = 90
b = 72.166β = 101.77
c = 62.547γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALEPACKdata scaling
Aimlessdata scaling
PDB_EXTRACTdata extraction
PHASERphasing
ARPmodel building
HKL-3000data processing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-23
    Type: Initial release
  • Version 1.1: 2015-10-07
    Changes: Data collection
  • Version 1.2: 2015-11-18
    Changes: Database references
  • Version 1.3: 2016-01-13
    Changes: Database references
  • Version 1.4: 2016-12-21
    Changes: Non-polymer description
  • Version 1.5: 2017-11-22
    Changes: Refinement description
  • Version 1.6: 2023-09-27
    Changes: Data collection, Database references, Refinement description
  • Version 1.7: 2023-11-15
    Changes: Data collection