3.A.1.209.1
MHC heterodimeric peptide exporter (TAP) (from cytoplasm to the endoplasmic reticulum) (TAP1=ABCB2; TAP2=ABCB3) (defects in TAP1 or TAP2 cause immunodeficiency) (TAP1/TAP2 is stabilized by tapasin isoforms 1, 2 and 3) (Raghuraman et al., 2002). TAP1 has 10 TMSs, 4 unique N-terminal TMSs and 6 TMSs that form the translocation pore with N- and C-termini in the cytosol (Schrodt et al., 2006). The TAP2 nucleotide binding site appears to be the main catalytic active site driving transport suggesting asymmetry in the transporter (Perria et al., 2006). The TAP complex shows strict coupling between peptide binding and ATP hydrolysis, revealing no basal ATPase activity in the absence of peptides (Herget et al., 2009).  There are three binding sites on TAP1 for tapasis which interconnects TAP and MHC class I, promotes TAP stability and facilitates heterodimerization (Leonhardt et al. 2014).  TAP is the target of GN1 (TC#8.B.25.1.1), a virally encoded protein inhibitor of viral peptide exposure on the cell surface (Verweij et al. 2008; Rufer et al. 2015). Tapasin (448 aas; O15533) stabilizes TAP2 (Papadopoulos and Momburg 2007). Tapasin is involved in the association of MHC class I with the transporter associated with antigen processing (TAP) and in the assembly of MHC class I with peptide (peptide loading). TAP plays a key role in the adaptive immune defense against infected or malignantly transformed cells by translocating proteasomal degradation products into the lumen of the endoplasmic reticulum for loading onto MHC class I molecules. TAP transports peptides from 8 to 40 residues, including even branched or modified molecules, suggestive of structural flexibility of the substrate-binding pocket. The bound peptides in side-chains' mobility was strongly restricted at the ends of the peptide, whereas the central region was flexible. Peptides bind to TAP in an extended kinked structure, analogous to those bound to MHC class I proteins (Herget et al., 2011). TAP translocates proteasomal degradation products from the cytosol into the lumen of the endoplasmic reticulum, where these peptides are loaded onto MHC class I molecules by a macromolecular peptide-loading complex (PLC) and subsequently shuttled to the cell surface for inspection by cytotoxic T lymphocytes. As a central adapter protein, tapasin (O15533) (Li et al. 2000) recruits other components of the PLC at the N-terminal domains of TAP. The alpha6/beta10-loop determines the nonsynonymous nucleotide binding of NBD1 and NBD2, whereas the switch region seems to play a critical role in regulating the functional cross-talk between the structural domains of TAP (Ehses et al. 2005). Koch et al. 2006 found that the N-terminal domains of human TAP1 and TAP2 independently bind to tapasin, thus providing two separate loading platforms for PLC assembly. Tapasin binding is dependent on the first N-terminal TMS of TAP1 and TAP2, demonstrating that these two helices contribute independently to the recruitment of tapasin and associated factors (Koch et al. 2006). The endoplasmic reticulum-resident human cytomegalovirus glycoprotein US6 (gpUS6) inhibits peptide translocation by the transporter associated with antigen processing (TAP) to prevent loading of major histocompatibility complex class I molecules and antigen presentation to CD8+ T cells. gpUS6 associates with preformed TAP1/2 heterodimers (Halenius et al. 2006). It is found in the blook brain barrier (Wang et al. 2024).  Nucleotide-dependent conformational changes direct peptide export by the transporter associated with antigen processing (TAP) (Lee et al. 2025).