title: Redox-regulated peptide transfer from the transporter associated with antigen processing to major histocompatibility complex class I molecules by protein disulfide isomerase.
abstract: Most antigenic peptides are generated by proteasomes in the cytosol and are transported by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum, where they bind with nascent major histocompatibilitiy complex class I molecule (MHC-I). Although the overall process of peptide-MHC-I complex assembly is well studied, the mechanism by which free peptides are delivered from TAP to MHC-I is unknown. In this study, we investigated the possible role of protein disulfide isomerase (PDI) as a peptide carrier between TAP and MHC-I. Analysis of PDI-peptide complexes reconstituted in vitro showed that PDI exhibits some degree of specificity for peptides corresponding to antigenic ligands of various human leukocyte antigen (HLA) alleles. Mutations of either anchor residues of the peptide ligand or the peptide-binding site of PDI inhibited the PDI-peptide interaction. The PDI-peptide interaction increased under reducing conditions, whereas binding of the peptide to PDI decreased under oxidizing conditions. TAP-associated PDI was predominantly present in the reduced form, whereas the MHC-I-associated PDI was present in the oxidized form. Further, upon binding of optimal peptides, PDI was released from TAP and sequentially associated with HLA-A2.1. Our data revealed a redox-regulated chaperone function of PDI in delivering antigenic peptides from TAP to MHC-I.
authors.affiliation: Department of Biological Sciences, National Creative Research Center for Antigen Presentation, Seoul National University, Seoul, South Korea.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Cho
authors.forename: Sunglim
authors.initials: S
authors.lastname: Cho
authors.forename: Seong-Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Changhoon
authors.initials: C
authors.lastname: Oh
authors.forename: Kwonyoon
authors.initials: K
authors.lastname: Kang
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Ryoo
authors.forename: Sungwook
authors.initials: S
authors.lastname: Lee
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
authors.forename: Kwangseog
authors.initials: K
authors.lastname: Ahn
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010084:Oxidation-Reduction; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; C477327:transporter associated with antigen processing (TAP); D019704:Protein Disulfide-Isomerases