Dynamic states of an MHC class I molecule during peptide exchange

Antigens of intracellular origin are processed then presented by proteins of the highly polymorphic major histocompatibility complex I (MHCI), thereby enabling T cell activation during an immune response. In particular, the peptide-exchange catalyst tapasin (Tsn) plays a critical role in shaping the pool of peptide antigens that ultimately reach the cell surface. Here, using disulfide bond engineering in conjunction with cryogenic electron microscopy (cryoEM) and molecular dynamics simulations, we provide evidence for partial collapse of the antigen binding groove during the peptide exchange process. An intermediate is formed that is characterized by interactions between the peptide's N-terminus and conserved tyrosine side chains in MHCI. Unfolding of the MHCI α1-helix in the Tsn-bound state is contrasted by a stable α2-helix that is kept in its native-like major conformation by the support of the large interface it entertains with the exchange catalyst. Helical disorder propensities and backbone flexibilities of the α1-helix are predicted to have increased during evolution, suggesting that the dynamic features introduced by polymorphic variation may have contributed to shaping the pool of antigens presented to T cells.