Getting in the groove: The selection of MHC-I antigen repertoires by molecular chaperones is governed by a network of protein dynamics

Abstract

Conformational dynamics have been implicated in regulating key aspects of class I major histocompatibility complex (MHC-I) function, including association with peptide antigens, and recognition of peptide-editing chaperones in an MHC-I allele-specific manner. Molecular dynamics simulations have provided insights into motions up to the microseconds timescale, however biophysical parameters characterizing these processes in solution are largely lacking. Here, we use solution NMR to explore how dynamics affect the interaction between peptide-loaded MHC-I (pMHC-I) and the chaperone TAPBPR, a structural homolog of tapasin which serves as the main catalytic enhancer of antigen loading in cells. We characterize motions up to the milliseconds timescale for a representative set of common mouse and human pMHC-I molecules exhibiting varying affinities for human TAPBPR in vitro. Our results establish that, in aqueous solution, pMHC-I molecules sample a minor conformation involving a network of dynamically coupled sites. The extent of dynamics at “hotspot” surfaces, including the heavy chain α2-1 helix, the pleated β-sheet underpinning the MHC-I groove, and α3 domain, correlate with the specificity of TAPBPR recognition by different alleles. Conversely, restriction of MHC-I groove dynamics through an engineered disulfide bond at the α2-1 helix abrogates interactions with TAPBPR, both in vitro and on a cellular membrane. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize distinct MHC-I alleles towards editing the repertoire of displayed antigens.