Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin

Abstract

MHC-I epitope presentation to CD8 + T cells is directly dependent on peptide loading and selection during antigen processing. However, the exact molecular bases underlying peptide selection and binding by MHC-I remain largely unknown. Within the peptideloading complex, the peptide editor tapasin is key to the selection of MHC-I-bound peptides. Here, we have determined an ensemble of crystal structures of MHC-I in complex with the peptide exchange-associated dipeptide GL, as well as the tapasin-associated scoop loop, alone or in combination with candidate epitopes. These results combined with mutation analyses allow us to propose a molecular model underlying MHC-I peptide selection by tapasin. The N termini of bound peptides most probably bind first in the N-terminal and middle region of the MHC-I peptide binding cleft, upon which the peptide C termini are tested for their capacity to dislodge the tapasin scoop loop from the F pocket of the MHC-I cleft. Our results also indicate important differences in peptide selection between different MHC-I alleles.MHC-I | tapasin | peptide editing | TAPBPR

TAPBPR Promotes Antigen Loading on MHC-I Molecules Using a Peptide Trap

“…A simultaneous publication from the same group of the tapasin-dependent PLC at low resolution seemed to support this mechanism, with the equivalent loop of tapasin partially modeled projecting into the F pocket (20) ( Fig. 1B, C-left ), while X-ray structures of MHC-I/dipeptide complexes together with a short hydrophobic peptide occupying the groove, derived from the tapasin loop, appear to show a stable, bound conformation (21). Recent studies have provided evidence that the TAPBPR G24-R36 loop influences peptide exchange on properly conformed MHC-I molecules, either by modulating peptide off-rates (22) or by acting as a leucine lever (23).…”

“…Recent studies have provided evidence that the TAPBPR G24-R36 loop influences peptide exchange on properly conformed MHC-I molecules, either by modulating peptide off-rates (22) or by acting as a leucine lever (23). In contrast, mutational insults to the “scoop” loop have only minor effects on tapasin-mediated intracellular processing of nascent MHC-I (21), while loop density is lacking in an independent crystal structure of the TAPBPR/MHC-I complex (18), likely due to disorder ( Fig. 1C-right ).…”

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

“…The primary aim of our contribution was to investigate the relationship of peptide-and binding groove-plasticity of HLA-B27 subtypes to the efficiency of negative T cell selection. Due to their distinct, peptide-independent conformational flexibility (17,(46)(47)(48), however, peptide-devoid HC/β 2 m complexes within a cell possess already the potential to differentially influence peptide-loading processes (63)(64)(65)(66)(67). This could be relevant for the subtype-dependent initiation of HLA-B * 27-associated diseases.…”

Peptide Presentation to T Cells: Solving the Immunogenic Puzzle

“…Cleaved peptides exit the proteasome and—should they survive further proteolytic degradation in the cytosol—are actively transported into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP). TAP forms a part of the peptide loading complex (PLC), the set of proteins and chaperones responsible for selecting peptides for binding empty MHC I within the ER . Bound peptides may be exchanged for other peptides during this process, and/or are N‐terminally trimmed by ER‐resident aminopeptidases, making the PLC responsible for editing the resulting MHC I repertoire.…”

“…Yet to paraphrase a famous physicist, the more we learn, the more we realize how much we do not know. That is to say, for many years we have relied upon empirical study of peptides to determine their immunogenicity, have unraveled the steps in antigen processing and peptide loading in great detail, have understood at a structural level MHC–peptide interactions and generalizations versus discrepancies in the docking of TCRs onto this complex, as well as the signaling cascade and cell fate that ensues . In characterizing thousands of T cell responses, immunologists have gained insight into phenomena such as immunodominance (the disproportionate skewing of responses in individuals and populations of individuals toward specific epitopes) and have begun to tread the tantalizing ground of harnessing T cells for tumor immunotherapy .…”