Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• The rat Major Histocompatibility Complex (MHC) class Ia molecule, RT1-Aa, exhibits an atypical ability to bind extended peptides.
• This includes the thirteen-residue maternally transmitted minor histocompatibility antigen, MTF-E, which possesses two arginine residues potentially serving as anchor points.

Purpose of the Study:

• To elucidate the structural basis of RT1-Aa binding to the long peptide MTF-E.
• To understand how the unique structure of the peptide-MHC (pMHC) complex influences T cell receptor (TCR) engagement.

Main Methods:

• X-ray crystallography was employed to determine the structure of the RT1-Aa-MTF-E complex at 2.55 Å resolution.
• Analysis of the crystal structure focused on peptide conformation and its presentation within the MHC binding groove.

Main Results:

• The crystal structure revealed that both termini of MTF-E are anchored within the RT1-Aa molecule, consistent with other class I MHCs.
• Intriguingly, the central residues of MTF-E adopted distinct bulged conformations in two independent pMHC complexes, driven by local environmental factors.
• The MTF-E epitope was found to be fully accessible within the predicted T cell receptor (TCR) binding site.

Conclusions:

• The observed structural flexibility of the RT1-Aa-MTF-E complex highlights a mechanism for generating diverse TCR responses.
• Chemically identical peptides can present structurally dissimilar epitopes, leading to differential TCR recognition and immune responses.