Antigenic Peptide Loading into Major Histocompatibility Complex Class I Is Driven by the Substrate N-Terminus

Abstract

Major histocompatibility complex class I(MHC-I), a key element of the acquired immune system, plays essential roles in activating CD8+ T cells by recognizing intracellularantigensderivedfrompathogensandcancer. Assembly ofMHC-I and antigen peptides is critical for the antigen presentation on the cell surface. However, the structural dynamics of antigenic peptide loading into MHC-I, at atomistic resolution, is still elusive. Here, by constructing a Markov state model (MSM)basedonlargescale all-atommoleculardynamics (MDs) simulations with an aggregated simulation time ∼24 μs, we reveal the detailed molecular mechanism underlying the peptide-loading dynamics into MHC-I and identify the key intermediates with associated thermodynamic/kinetic properties. Furthermore, we examine how the chaperone tapasin-binding protein related (TAPBPR) participates in promoting the peptide loading, and the results showthat TAPBPR, by binding to the F pocket, allosterically modulates the structures of the distant pocket B, resulting in formation of a peptide-receptive conformation ideal for accommodating the incoming peptide N-terminus. This studyprovides fundamental structural insights for the peptide loading into MHC-I in both chaperone uncatalyzed and catalyzed contexts.