Structure of the TAPBPR–MHC I complex defines the mechanism of peptide loading and editing

• Published in: Science (American Association for the Advancement of Science) Vol. 358; no. 6366; pp. 1060 - 1064
• Main Authors: Thomas, Christoph, Tampé, Robert
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 24.11.2017; The American Association for the Advancement of Science
• Subjects: Adaptive immunity; Affinity; Antigen processing; Antigens; beta 2-Microglobulin - chemistry; beta 2-Microglobulin - ultrastructure; Biocatalysis; Catalysis; CD8 antigen; Chaperones; Crystal defects; Crystal structure; Crystallography, X-Ray; Cytotoxicity; Editing; Endoplasmic reticulum; Epitopes; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - ultrastructure; Humans; Immune response; Immune system; Immunity; Immunoglobulins - chemistry; Immunoglobulins - ultrastructure; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Membrane Proteins - chemistry; Membrane Proteins - ultrastructure; Mutation; Peptides; Peptides - chemistry; Proofreading; Protein Conformation; Tapasin
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aao6001

Adaptive immunity is shaped by a selection of peptides presented on major histocompatibility complex class I (MHC I) molecules. The chaperones Tapasin (Tsn) and TAP-binding protein–related (TAPBPR) facilitate MHC I peptide loading and high-affinity epitope selection. Despite the pivotal role of Tsn and TAPBPR in controlling the hierarchical immune response, their catalytic mechanism remains unknown. Here, we present the x-ray structure of the TAPBPR–MHC I complex, which delineates the central step of catalysis. TAPBPR functions as peptide selector by remodeling the MHC I α2-1-helix region, stabilizing the empty binding groove, and inserting a loop into the groove that interferes with peptide binding. The complex explains how mutations in MHC I–specific chaperones cause defects in antigen processing and suggests a unifying mechanism of peptide proofreading.