Abstract
The transporter associated with antigen processing (TAP) is an ATP-binding cassette (ABC) transporter essential to cellular immunity against viral infection. Some persistent viruses have evolved strategies to inhibit TAP so that they may go undetected by the immune system. The herpes simplex virus for example evades immune surveillance by blocking peptide transport with a small viral protein ICP47. In this study, we determined the structure of human TAP bound to ICP47 by electron cryo-microscopy (cryo-EM) to 4.0 Å. The structure shows that ICP47 traps TAP in an inactive conformation distinct from the normal transport cycle. The specificity and potency of ICP47 inhibition result from contacts between the tip of the helical hairpin and the apex of the transmembrane cavity. This work provides a clear molecular description of immune evasion by a persistent virus. It also establishes the molecular structure of TAP to facilitate mechanistic studies of the antigen presentation process.
Highlights
Cytotoxic T cells detect and eliminate infected cells by recognizing viral peptides displayed on the cell surface by major histocompatibility complex (MHC-I) molecules (Blum et al, 2013)
The transporter associated with antigen processing (TAP) transports these cytosolic peptides into the endoplasmic reticulum (ER) lumen, where a multi-component peptide-loading complex facilitates peptidebinding to nascent MHC-I molecules (Neefjes et al, 1993; Shepherd et al, 1993)
As the ordered region of the TAP/ICP47 complex has a molecular mass of only 130 kDa and exhibits a pseudo-twofold symmetry, two factors likely limiting resolution are the accuracy with which the noisy cryo-electron microscopy (cryo-EM) images of single particles can be aligned and the ability to distinguish pseudo-symmetrically related views
Summary
Cytotoxic T cells detect and eliminate infected cells by recognizing viral peptides displayed on the cell surface by major histocompatibility complex (MHC-I) molecules (Blum et al, 2013). Similar to other ABC transporters, it contains two nucleotide-binding domains (NBDs) that hydrolyze ATP and two transmembrane domains (TMDs) that bind the substrate Both TAP1 and TAP2 contain an N-terminal transmembrane region (TMD0) that interacts with tapasin to form the larger peptide-loading complex (Hulpke et al, 2012; Procko et al, 2005). The only sequence constraint found for human TAP is a preference for a hydrophobic or basic residue at the C-terminus (Momburg et al, 1994b) This peptide preference complements MHC-I specificity in that an acidic C-terminus is rarely seen in MHC-I presented peptides (Rammensee et al, 1999). We present a 4.0 Acryo-EM reconstruction of the human TAP/ICP47 complex and describe the specific atomic interactions that allow the viral peptide to bind tightly to TAP and lock it in an inactive state
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