CryoEM structure of an MHC- I/TAPBPR peptide- bound intermediate reveals the mechanism of antigen proofreading

• 成果类型: Article
• 署名作者: Sun, Yi; Pumroy, Ruth A.; Mallik, Leena; Chaudhuri, Apala; Wang, Chloe; Hwang, Daniel; Danon, Julia N.; Goli, Kimia Dasteh; Moiseenkova-Bell, Vera Y.; Sgourakis, Nikolaos G.
• 署名单位: University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10167
• DOI: 10.1073/pnas.2416992122
• 发表日期: 2025-01-14
• 关键词: class-i molecules; complex defines; tapasin; tapbpr; exchange; polymorphisms; repertoire; DYNAMICS; receptor; gene

摘要

Class I major histocompatibility complex (MHC-I) proteins play a pivotal role in adaptive immunity by displaying epitopic peptides to CD8+ T cells. The chaperones tapasin and TAPBPR promote the selection of immunogenic antigens from a large pool of intracellular peptides. Interactions of chaperoned MHC-I molecules with incoming peptides are transient in nature, and as a result, the precise antigen proofreading mechanism remains elusive. Here, we leverage a high- fidelity TAPBPR variant and conformationally stabilized MHC-I, to determine the solution structure of the human antigen editing complex bound to a peptide decoy by cryogenic electron microscopy (cryo-EM) at an average resolution of 3.0 & Aring;. Antigen proofreading is mediated by transient interactions formed between the nascent peptide binding groove with the P2/P3 peptide anchors, where conserved MHC-I residues stabilize incoming peptides through backbone- focused contacts. Finally, using our high- fidelity chaperone, we demonstrate robust peptide exchange on the cell surface across multiple clinically relevant human MHC-I allomorphs. Our work has important ramifications for understanding the selection of immunogenic epitopes for T cell screening and vaccine design applications.