As a centerpiece of the peptide loading complex, the heterodimeric ABC transporter TAP translocates proteasomal degradation products into the ER lumen, where they are loaded onto MHC I molecules. Within the cellular process of antigen presentation via major histocompatibility complex class I (MHC I) molecules, the transporter associated with antigen processing TAP is responsible for antigen compartmentalization. These new insights into the ICP47 inhibition mechanism can be applied for future structural analyses of the TAP complex. A per se destabilizing active domain inhibits the function of TAP, whereas a conserved C-terminal region additionally stabilizes the transporter. Based on our findings, we propose a dual interaction mechanism for ICP47. Binding of the active domain of ICP47 arrests TAP in an open inward facing conformation rendering the complex inaccessible for other viral factors. We unveiled a conserved region next to the active domain of ICP47 as essential for the complete stabilization of the TAP complex. ICP47-TAP fusion complexes are arrested in a stable conformation, as demonstrated by MHC I surface expression, melting temperature, and the mutual exclusion of herpesviral TAP inhibitors. These fusion complexes allowed us to determine the direction and positioning in the central cavity of TAP.
Here, we report on a thermostable ICP47-TAP complex, generated by fusion of different ICP47 fragments.
The herpesviral ICP47 inhibits TAP function, thereby suppressing an adaptive immune response. As a centerpiece of antigen processing, the ATP-binding cassette transporter associated with antigen processing (TAP) became a main target for viral immune evasion.
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