posters 5th Asia-Pacific NMR Symposium 2013

The functional and structural role of cysteine residues in Toll-like receptor signalling adaptor MAL/ TIRAP (#159)

Peter Lavrencic 1 , Thomas Ve 1 , Mehdi Mobli 1 2 3 , Bostjan Kobe 1 3 4
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
  2. Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
  3. Institute for Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
  4. Australian Infections Disease Research Centre, The University of Queensland, Brisbane, QLD, Australia

MyD88 adaptor protein (MAL) / TIR domain-containing adaptor protein (TIRAP) is a key player in the Toll-like receptor (TLR) signalling cascade of the human immune system. As the TLRs are stimulated, the Toll/ interleukin-1 receptor (TIR) domain of MAL binds to the intracellular domain of the TLR to relay the signal to MyD88 and in turn activate the production of NF-kB and cytokines.

 Our group recently solved the crystal structure of MAL, which showed that specific cysteines formed two disulphide bonds that could contribute to the stability of the protein. However, it has been hypothesised that those cysteines may in fact participate in redox-mediated conformational change of the protein. In addition, another pair of cysteines that are in close proximity to each other, while not forming a disulfide bond, may be involved in binding and signal transduction.

 Based on these observations, the sample conditions were optimised for NMR and the backbone assigned to give insight into the redox state of the cysteine residues in solution. Future work will be focused on the functional role of cysteines in the MAL protein.