Nevertheless, the potential timescale of searching the myriad possible conformations of a protein as noted by Levinthal ( 3, 4) raised a conundrum solved only partially by the recognition of the contribution of protein nucleation regions and folding landscapes ( 5, 6) to the descent along an energy funnel to achieve a final stable structure ( 7). Recent studies suggest that these two chaperone/catalysts exploit structural flexibility and dynamics to stabilize MHC molecules and facilitate peptide loading.Ĭlassical experiments indicate that proteins arrive at their stable three-dimensional conformation at their lowest Gibbs free energy, achieved as a result of their primary amino acid sequence and their interactions with solvent ( 1, 2). Regions of structural conservation among species suggest that TAPBPR and tapasin have evolved to satisfy functional complexities demanded by the enormous polymorphism of MHC I molecules. Recent structural and dynamic studies of TAPBPR reveal details of its function and reflect on mechanisms common to tapasin. Peptide loading occurs in an antigen presentation pathway that includes either the multimolecular peptide loading complex (PLC) or a single chain chaperone/catalyst, TAP binding protein, related, TAPBPR, that mimics a key component of the PLC, tapasin. This review focuses on MHC I molecules that coordinately fold to bind self or foreign peptides for such surface display. Immune recognition by T lymphocytes and natural killer (NK) cells is in large part dependent on the identification of cell surface MHC molecules bearing peptides generated from either endogenous (MHC I) or exogenous (MHC II) dependent pathways.
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