Structure of an MHC I–tapasin–ERp57 editing complex defines chaperone promiscuity

Abstract

Adaptive immunity depends on cell surface presentation of antigenic peptides by major histocompatibility complex class I (MHC I) molecules and on stringent ER quality control in the secretory pathway. The chaperone tapasin in conjunction with the oxidoreductase ERp57 is crucial for MHC I assembly and for shaping the epitope repertoire for high immunogenicity. However, how the tapasin–ERp57 complex engages MHC I clients has not yet been determined at atomic detail. Here, we present the 2.7-Å crystal structure of a tapasin–ERp57 heterodimer in complex with peptide-receptive MHC I. Our study unveils molecular details of client recognition by the multichaperone complex and highlights elements indispensable for peptide proofreading. The structure of this transient ER quality control complex provides the mechanistic basis for the selector function of tapasin and showcases how the numerous MHC I allomorphs are chaperoned during peptide loading and editing.

Mass spectrometric profiling of HLA-B44 peptidomes provides evidence for tapasin-mediated tryptophan editing

“…The F-pocket, formed by the α 2-1 domain of the HLA class I peptide-binding groove, accommodates C-terminal residues of peptides (14, 34). The editing loop at the N-terminus of tapasin sits on top of the F pocket, while a β hairpin element of tapasin contacts the base of the F pocket, resulting in a "clamp" like binding of the tapasin to the α 2-1 domain of the MHC class I peptide binding groove (11,12).…”

“…The editing loop of tapasin has been suggested to stabilize the widening of the F pocket creating a peptide-receptive conformation and tapasin also shields the C-terminus of an incoming peptide ligand (12). The increased detection of B*44:05 peptides with Cterminal tryptophans in the presence of tapasin suggests that tapasin-mediated widening of the F pocket is important to facilitate the binding of bulky amino acids such as tryptophan.…”

The mode of action of tapasin on major histocompatibility class I (MHC-I) molecules

“…Tapasin is colored by pLDDT confidence values, denoting regions from low ( red , yellow ) to high confidence ( cyan , blue ) in the prediction. B , aligned structures of MHC-I-tapasin derived from PLC (PDB ID 7QPD) ( 37 ), H2-D b -tapasin-ERp57 complex (PDB ID 7QNG) ( 38 ), and the B44:05-T73C -6mer-tapasin complex (PDB ID: 7TUE) ( 39 ). The color of heavy chain for A∗03:01, H2-D b , and B∗44:05 are gray , light blue , and wheat , respectively.…”

“…It is of note that during the process of revising this review, three high-resolution structures of Tsn in complex with MHC-I were published ( 37 , 38 , 39 ) ( Fig. 3 B ).…”

The ER folding sensor UGGT1 acts on TAPBPR-chaperoned peptide-free MHC I

“…The catalytic principles of peptide optimization have been revealed by crystal structures of the TAPBPR-MHC I complex (Jiang et al , 2017; Thomas & Tampé, 2017). Insights into the interaction characteristics between Tsn and peptide-receptive MHC I have been gained by structures of Tsn-ERp57-H2-D b (Müller et al , 2022) and Tsn-HLA-B*44:05 (Jiang et al , 2022), respectively. While Tsn is a key constituent of the PLC, TAPBPR functions outside the PLC and downstream of Tsn in the secretory pathway, even beyond the ER in the Golgi compartment (Boyle et al ., 2013).…”