N��-terminal acetylation for T cell recognition: molecular basis of MHC class I-restricted n��-acetylpeptide presentation.

As one of the most common posttranslational modifications (PTMs) of eukaryotic proteins, N(α)-terminal acetylation (Nt-acetylation) generates a class of N(α)-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(α)-acetylpeptides remains largely unknown. In this study, we determined a high-resolution crystallographic structure of HLA (HLA)-B*3901 complexed with an N(α)-acetylpeptide derived from natural cellular processing, also in comparison with the unmodified-peptide complex. Unlike the α-amino-free P1 residues of unmodified peptide, of which the α-amino group inserts into pocket A of the Ag-binding groove, the N(α)-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 α1-helix of HLA-B*3901, which may impact the T cell engagement. The thermostability measurements of complexes between N(α)-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(α)-acetylpeptide-specific presentation by classical MHC class I molecules and shed light on the potential of acetylepitope-based immune intervene and vaccine development.

Structure deposition and release

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