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

Sun, Y.; Pumroy, R. A.; Mallik, L.; Chaudhuri, A.; Wang, C.; Hwang, D.; Danon, J.; Dasteh Goli, K.; Moiseenkova-Bell, V.; Sgourakis, N.

doi:10.1101/2024.08.05.606663

bioRxiv · 10.1101/2024.08.05.606663

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

Sun, Y.·Pumroy, R. A.·Mallik, L.·Chaudhuri, A.·Wang, C.·Hwang, D.·Danon, J.·Dasteh Goli, K.·Moiseenkova-Bell, V.·Sgourakis, N.

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Abstract

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 [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.

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Sun, Y., Pumroy, R. A., Mallik, L., Chaudhuri, A., Wang, C., Hwang, D., Danon, J., Dasteh Goli, K., Moiseenkova-Bell, V., Sgourakis, N.. 2024-08-07. CryoEM structure of an MHC-I/TAPBPR peptide bound intermediate reveals the mechanism of antigen proofreading. https://doi.org/10.1101/2024.08.05.606663

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