title: An annular lipid belt is essential for allosteric coupling and viral inhibition of the antigen translocation complex TAP (transporter associated with antigen processing).
abstract: The transporter associated with antigen processing (TAP) constitutes a focal element in the adaptive immune response against infected or malignantly transformed cells. TAP shuttles proteasomal degradation products into the lumen of the endoplasmic reticulum for loading of major histocompatibility complex (MHC) class I molecules. Here, the heterodimeric TAP complex was purified and reconstituted in nanodiscs in defined stoichiometry. We demonstrate that a single heterodimeric core-TAP complex is active in peptide binding, which is tightly coupled to ATP hydrolysis. Notably, with increasing peptide length, the ATP turnover was gradually decreased, revealing that ATP hydrolysis is coupled to the movement of peptide through the ATP-binding cassette transporter. In addition, all-atom molecular dynamics simulations show that the observed 22 lipids are sufficient to form an annular belt surrounding the TAP complex. This lipid belt is essential for high affinity inhibition by the herpesvirus immune evasin ICP47. In conclusion, nanodiscs are a powerful approach to study the important role of lipids as well as the function, interaction, and modulation of the antigen translocation machinery.
authors.affiliation: From the Institute of Biochemistry, Biocenter, Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt/M..
authors.forename: Sabine
authors.initials: S
authors.lastname: Eggensperger
authors.affiliation: the Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780 Bochum, and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fisette
authors.affiliation: From the Institute of Biochemistry, Biocenter, Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt/M..
authors.forename: David
authors.initials: D
authors.lastname: Parcej
authors.affiliation: the Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780 Bochum, and.
authors.forename: Lars V
authors.initials: LV
authors.lastname: Schäfer
authors.affiliation: From the Institute of Biochemistry, Biocenter, Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt/M., the Cluster of Excellence-Macromolecular Complexes, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt/M., Germany tampe@em.uni-frankfurt.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017951:Antigen Presentation; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008563:Membrane Lipids / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D008563:Membrane Lipids; D046912:Multiprotein Complexes; D010455:Peptides; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases
keywords: ATP-binding Cassette Transporter; Antigen Processing; Herpesvirus; Lipid Bilayer; Membrane Protein; Membrane Transport; Membrane Transporter Reconstitution; Peptide Transport; Transporter