Nα-Terminal Acetylation for T Cell Recognition: Molecular Basis of MHC Class I-Restricted Nα-Acetylpeptide Presentation

As one of the most common posttranslational modifications (PTMs) of eukaryotic proteins, N-alpha-terminal acetylation (Nt-acetylation) generates a class of N-alpha-acetylpeptides that are known to be presented by MHC class I at the cell surface. Although such PTM plays a pivotal role in adjusting proteolysis, the molecular basis for the presentation and T cell recognition of N-alpha-acetylpeptides remains largely unknown. In this study, we determined a high-resolution crystallographic structure of HLA (HLA)-B*3901 complexed with an N-alpha-acetylpeptide derived from natural cellular processing, also in comparison with the unmodified-peptide complex. Unlike the alpha-amino-free P1 residues of unmodified peptide, of which the alpha-amino group inserts into pocket A of the Ag-binding groove, the N-alpha-linked acetyl of the acetylated P1-Ser protrudes out of the groove for T cell recognition. Moreover, the Nt-acetylation not only alters the conformation of the peptide but also switches the residues in the alpha 1-helix of HLA-B*3901, which may impact the T cell engagement. The thermostability measurements of complexes between N-alpha-acetylpeptides and a series of MHC class I molecules derived from different species reveal reduced stability. Our findings provide the insight into the mode of N-alpha-acetylpeptide-specific presentation by classical MHC class I molecules and shed light on the potential of acetylepitope-based immune intervene and vaccine development.