Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules
Lan, Huan and Abualrous, Esam T. and Sticht, Jana and Fernandez, Laura Maria Arroyo and Werk, Tamina and Weise, Christoph and Ballaschk, Martin and Schmieder, Peter and Loll, Bernhard and Freund, Christian – 2021
The repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface is tailored by the ER-resident peptide loading complex (PLC), which contains the exchange catalyst tapasin. Tapasin stabilizes MHC-I molecules and promotes the formation of stable peptide-MHC-I (pMHC-I) complexes that serve as T cell antigens. Exchange of suboptimal by high-affinity ligands is catalyzed by tapasin, but the underlying mechanism is still elusive. Here we analyze the tapasin-induced changes in MHC-I dynamics, and find the catalyst to exploit two essential features of MHC-I. First, tapasin recognizes a conserved allosteric site underneath the ?2-1-helix of MHC-I, loosening the MHC-I F-pocket region that accomodates the C-terminus of the peptide. Second, the scoop loop1120 of tapasin relies on residue L18 to target the MHC-I F-pocket, enabling peptide exchange. Meanwhile, tapasin residue K16 plays an accessory role in catalysis of MHC-I allotypes bearing an acidic F-pocket. Thus, our results provide an explanation for the observed allele-specificity of catalyzed peptide exchange.