The 14-3-3/SLP76 protein–protein interaction in T-cell receptor signalling: a structural and biophysical characterization

Lorenzo Soini, Seppe Leysen, Jeremy Davis, Marta Westwood, Christian Ottmann (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The SH2 domain-containing protein of 76 kDa, SLP76, is an important adaptor protein that coordinates a complex protein network downstream of T-cell receptors (TCR), ultimately regulating the immune response. Upon phosphorylation on Ser376, SLP76 interacts with 14-3-3 adaptor proteins, which leads to its proteolytic degradation. This provides a negative feedback mechanism by which TCR signalling can be controlled. To gain insight into the 14-3-3/SLP76 protein–protein interaction (PPI), we have determined a high-resolution crystal structure of a SLP76 synthetic peptide containing Ser376 with 14-3-3σ. We then characterized its binding to 14-3-3 proteins biophysically by means of fluorescence polarization and isothermal titration calorimetry. Furthermore, we generated two recombinant SLP76 protein constructs and characterized their binding to 14-3-3. Our work lays the foundation for drug design efforts aimed at targeting the 14-3-3/SLP76 interaction and, thereby, TCR signalling.

Original languageEnglish
Number of pages11
JournalFEBS Letters
VolumeXX
Issue numberXX
DOIs
Publication statusAccepted/In press - 7 Nov 2020

Keywords

  • isothermal titration calorimetry
  • protein constructs
  • surface plasmon resonance
  • TCR signalling and 14-3-3
  • X-ray protein crystallography

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