title: Assembly of the MHC I peptide-loading complex determined by a conserved ionic lock-switch.
abstract: Salt bridges in lipid bilayers play a decisive role in the dynamic assembly and downstream signaling of the natural killer and T-cell receptors. Here, we describe the identification of an inter-subunit salt bridge in the membrane within yet another key component of the immune system, the peptide-loading complex (PLC). The PLC regulates cell surface presentation of self-antigens and antigenic peptides via molecules of the major histocompatibility complex class I. We demonstrate that a single salt bridge in the membrane between the transporter associated with antigen processing TAP and the MHC I-specific chaperone tapasin is essential for the assembly of the PLC and for efficient MHC I antigen presentation. Molecular modeling and all-atom molecular dynamics simulations suggest an ionic lock-switch mechanism for the binding of TAP to tapasin, in which an unfavorable uncompensated charge in the ER-membrane is prevented through complex formation. Our findings not only deepen the understanding of the interaction network within the PLC, but also provide evidence for a general interaction principle of dynamic multiprotein membrane complexes in immunity.
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blees
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, D-44780 Bochum, Germany.|Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, D-60438 Frankfurt am Main, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Reichel
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Trowitzsch
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, D-44780 Bochum, Germany.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fisette
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Abele
authors.affiliation: Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, D-60438 Frankfurt am Main, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hummer
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, D-44780 Bochum, Germany.
authors.forename: Lars V
authors.initials: LV
authors.lastname: Schäfer
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.|Cluster of Excellence-Macromolecular Complexes, Goethe-University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics*; D002462:Cell Membrane; D015870:Gene Expression; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D055672:Static Electricity; D014162:Transfection
chemical_list: D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D046912:Multiprotein Complexes; D010455:Peptides; D011994:Recombinant Proteins; C107762:tapasin