Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules

H. Lan; E.T. Abualrous; J. Sticht; L.M. Arroyo-Fernandez; T. Werk; C. Weise; M. Ballaschk; P. Schmieder; B. Loll; C. Freund*

Nat. Commun. 12, 4236 (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 α2-1-helix of MHC-I, ‘loosening’ the
MHC-I F-pocket region that accomodates the C-terminus of the peptide. Second, the scoop
loop11–20 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.