Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep19085
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- Deutsche Forschungsgemeinschaft (DFG) through Cluster of Excellence RESOLV [EXC 1069, SFB 807]
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Immune recognition of infected or malignantly transformed cells relies on antigenic peptides exposed at the cell surface by major histocompatibility complex class I (MHC I) molecules. Selection and loading of peptides onto MHC I is orchestrated by the peptide-loading complex (PLC), a multiprotein assembly whose structure has not yet been resolved. Tapasin, a central component of the PLC, stabilises MHC I and catalyses the exchange of low-affinity against high-affinity, immunodominant peptides. Up to now, the molecular basis of this peptide editing mechanism remained elusive. Here, using all-atom molecular dynamics (MD) simulations, we unravel the atomic details of how tapasin and antigen peptides act on the MHC I binding groove. Force distribution analysis reveals an intriguing molecular tug-of-war mechanism: only high-affinity peptides can exert sufficiently large forces to close the binding groove, thus overcoming the opposite forces exerted by tapasin to open it. Tapasin therefore accelerates the release of low-affinity peptides until a high-affinity antigen binds, promoting subsequent PLC breakdown. Fluctuation and entropy analyses show how tapasin chaperones MHC I by stabilising it in a peptide-receptive conformation. Our results explain previous experiments and mark a key step towards a better understanding of adaptive immunity.
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