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

DOI: 10.1002/1873-3468.13993 DOI Help

Authors: Lorenzo Soini (Eindhoven University of Technology; UCB Celltech) , Seppe Leysen (UCB Celltech) , Jeremy Davis (UCB Celltech) , Marta Westwood (UCB Celltech) , Christian Ottmann (Eindhoven University of Technology)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Febs Letters , VOL 10

State: Published (Approved)
Published: November 2020

Open Access Open Access

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.

Journal Keywords: isothermal titration calorimetry; protein constructs; surface plasmon resonance; TCR signalling and 14‐3‐3; X‐ray protein crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 25/11/2020 13:33


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)