An annular lipid belt is essential for allosteric coupling and viral inhibition of the antigen translocation complex TAP [Lipids]

October 10th, 2014 by Eggensperger, S., Fisette, O., Parceȷ, D., Schafer, L. V., Tampe, R.

The transporter associated with antigen processing (TAP) constitutes a focal element in the adaptive immune response against infected or malignantly transformed cells. TAP shuttles proteasomal degradation products into the ER lumen for loading of major histocompatibility complex (MHC) class I molecules. Here, the heterodimeric TAP complex was purified and reconstituted in nanodiscs in defined stoichiometry. We demonstrate that a single heterodimeric coreTAP complex is active in peptide binding, which is tightly coupled to ATP hydrolysis. Notably, with increasing peptide length, the ATP turnover was gradually decreased, revealing that ATP hydrolysis is coupled to the movement of peptide trough the ABC transporter. In addition, all-atom molecular dynamics (MD) simulations show that the observed 22 lipids are sufficient to form an annular belt surrounding the TAP complex. This lipid belt is essential for high-affinity inhibition by the herpesviral immune evasin ICP47. In conclusion, nanodiscs are a powerful approach to study the important role of lipids and function, interaction, and modulation of the antigen translocation machinery.