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The transporter associated with antigen processing (TAP) translocates antigenic peptides into the endoplasmic reticulum (ER) lumen for loading onto MHC class I molecules. This is a key step in the control of viral infections through CD8+ T-cells. The herpes simplex virus type-1 encodes an 88 amino acid long species-specific TAP inhibitor, ICP47, that functions as a high affinity competitor for the peptide binding site on TAP. It has previously been suggested that the inhibitory function of ICP47 resides within the N-terminal region (residues 1–35). Here we show that mutation of the highly conserved  50 PLL 52  motif within the central region of ICP47 attenuates its inhibitory capacity. Taking advantage of the human cytomegalovirus-encoded TAP inhibitor US6 as a luminal sensor for conformational changes of TAP, we demonstrated that the  50 PLL 52  motif is essential for freezing of the TAP conformation. Moreover, hierarchical functional interaction sites on TAP dependent on  50 PLL 52  could be defined using a comprehensive set of human-rat TAP chimeras. This data broadens our understanding of the molecular mechanism underpinning TAP inhibition by ICP47, to include the  50 PLL 52  sequence as a stabilizer that tethers the TAP-ICP47 complex in an inward-facing conformation.

A highly conserved sequence of the viral TAP inhibitor ICP47 is required for freezing of the peptide transport cycle