Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selection

Abstract

We examined interactions in a soluble tapasin (TPN)/HLA‐B*0801 complex to gain mechanistic insights into the functions of TPN. Results show that TPN acts as a chaperone by increasing the ratio of active‐to‐inactive peptide‐deficient HLA‐B*0801 molecules in solution. TPN causes peptides to associate and dissociate faster owing to its effect on widening the binding groove of HLA‐B*0801 molecules. Our data indicate that a TPN‐assisted mechanism of peptide selection relies on disruption of conserved hydrogen bonds at the C‐terminal end of the groove. Peptide sequence‐dependent interactions along the entire length of the groove also play a role in this mechanism. We suggest that TPN influences presentation of antigenic peptides according to a mechanistically complicated process in which bound candidate peptides that are unable to conformationally disengage TPN from class I molecules are excluded from the repertoire. Overall, these studies unify our understanding of the functions of TPN.