Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules
Lan, Huan, Abualrous, Esam T., Sticht, Jana, Fernandez, Laura Maria Arroyo, Werk, Tamina, Weise, Christoph, Ballaschk, Martin, Schmieder, Peter, 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.