9c96 | pdb_00009c96
Cryo-EM structure of TAP binding protein related (TAPBPR) in complex with HLA-A*02:01 bound to a suboptimal peptide.
Structural highlights
FunctionPublication Abstract from PubMedClass 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 A. 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. CryoEM structure of an MHC-I/TAPBPR peptide-bound intermediate reveals the mechanism of antigen proofreading.,Sun Y, Pumroy RA, Mallik L, Chaudhuri A, Wang C, Hwang D, Danon JN, Dasteh Goli K, Moiseenkova-Bell VY, Sgourakis NG Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2416992122. doi: , 10.1073/pnas.2416992122. Epub 2025 Jan 9. PMID:39786927[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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