title: Single residue within the antigen translocation complex TAP controls the epitope repertoire by stabilizing a receptive conformation.
abstract: The recognition of virus infected or malignantly transformed cells by cytotoxic T lymphocytes critically depends on the transporter associated with antigen processing (TAP), which delivers proteasomal degradation products into the endoplasmic reticulum lumen for subsequent loading of major histocompatibility complex class I molecules. Here we have identified a single cysteinyl residue in the TAP complex that modulates peptide binding and translocation, thereby restricting the epitope repertoire. Cysteine 213 in human TAP2 was found to be part of a newly uncovered substrate-binding site crucial for peptide recognition. This residue contacts the peptide in the binding pocket in an orientated manner. The translocation complex can be reversibly inactivated by thiol modification of this cysteinyl residue. As part of an unexpected mechanism, this residue is crucial in complementing the binding pocket for a given subset of epitopes as well as in maintaining a substrate-receptive conformation of the translocation complex.
authors.affiliation: Institute of Biochemistry, Center for Membrane Proteomics, and Cluster of Excellence Frankfurt-Macromolecular Complexes, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt/Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Baldauf
authors.forename: Susanne
authors.initials: S
authors.lastname: Schrodt
authors.forename: Meike
authors.initials: M
authors.lastname: Herget
authors.forename: Joachim
authors.initials: J
authors.lastname: Koch
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008958:Models, Molecular; D016296:Mutagenesis; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D018528:ATP-Binding Cassette Transporters; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; C477327:transporter associated with antigen processing (TAP); D003545:Cysteine