MHC class II complexes sample intermediate states along the peptide exchange pathway.

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• Peptide-MHCII complexes (pMHCIIs) present antigens to T cells, a critical process for adaptive immunity.
• The conformational dynamics governing peptide exchange in pMHCIIs are not well understood.
• Understanding these dynamics is crucial for deciphering T cell surveillance and immune responses.

Purpose of the Study:

• To elucidate the conformational dynamics of peptide exchange in peptide-MHCII complexes (pMHCIIs).
• To identify the distinct pathways involved in both intrinsic and HLA-DM-catalyzed peptide exchange.
• To investigate the role of pMHCII conformation in shaping immune responses and the impact of allelic variation.

Main Methods:

• Utilized Nuclear Magnetic Resonance (NMR)-detected hydrogen-deuterium (H/D) exchange.
• Performed extensive molecular dynamics (MD) simulations (275 microseconds aggregate).
• Applied Markov modeling analysis to simulation data.

Main Results:

• Identified that stable pMHCIIs spontaneously sample intermediate conformations essential for peptide exchange.
• Revealed two major peptide exchange pathways: intrinsic exchange governed by ground state stability and HLA-DM-catalyzed exchange linked to rare intermediate conformations.
• Demonstrated that helix-destabilizing mutants favor the HLA-DM-catalyzed pathway, validating the proposed model.

Conclusions:

• The kinetic stability of the pMHCII ground state dictates intrinsic peptide exchange rates.
• A rare intermediate conformation is critical for the HLA-DM-catalyzed peptide exchange pathway.
• Conformational dynamics and allelic variation in MHC influence T cell recognition and immune responses.