Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Investigating mechanisms of T cell Receptor activation (#109)

Nick J Chandler 1 2 , Matthew E Call 1 2 , Melissa J Call 1 2
  1. Walter and Eliza Hall Institute of medical research, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia

The ability of a T cell to recognise foreign peptides on the surface of infected or transformed cells originates with the T-cell receptor (TCR). The TCR is an octameric complex composed of the ligand binding TCRαβ chains and the CD3 signalling modules CD3γε, CD3δε, ζζ. The TCRαβ chains possess no intrinsic signalling capacity, and it is currently unknown how they convey ligand-specific information to the CD3 signalling modules in order to activate downstream signalling cascades. Recently published work from our lab (Krshnan, L., et al. 2016) identified a core TCRαβ transmembrane (TM) interface which we propose could act as a conduit through which structural changes induced by ligand binding could be communicated to the CD3 modules. To address whether structural changes are required for signalling, engineered TCRαβ receptors are being designed to disrupt or reinforce the interface. We have made a series of constructs that mutate the three highly conserved polar residues in the core of the structure to loosen the interface.  To strengthen the interface, we are investigating two approaches to lock the receptor; from the extracellular side using cysteine crosslinking and from the intracellular side using leucine zippers. Quantitative signalling analysis of this collection of engineered receptors will inform on the structural requirements of TCR signal transduction.

  1. KRSHNAN, L., PARK, S., IM, W., CALL, M. J. & CALL, M. E. 2016. A conserved alpha beta transmembrane interface forms the core of a compact T-cell receptor-CD3 structure within the membrane. Proceedings of the National Academy of Sciences of the United States of America, 113, E6649-E6658.