Direct evidence for conformational dynamics in major histocompatibility complex class I molecules.

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• Major histocompatibility complex class I (MHC I) molecules present peptides to cytotoxic T lymphocytes, a critical step in adaptive immunity.
• MHC I molecules exhibit peptide specificity, but the underlying selection mechanism and molecular basis for this discrimination remain largely unknown.
• The dynamic nature and conformational plasticity of MHC I molecules are hypothesized to be involved in peptide selection but have been difficult to study due to instability.

Purpose of the Study:

• To investigate the dynamic conformational changes of MHC I molecules.
• To elucidate the mechanism by which MHC I molecules select specific peptides for presentation.
• To understand the role of MHC I plasticity in peptide binding and antigen presentation.

Main Methods:

• Refolding of MHC I proteins with UV-light-cleavable peptides.
• Comparison of peptide-loaded MHC I with peptide-receptive MHC I using hydrogen-deuterium exchange mass spectrometry (HDX-MS).
• Analysis of deuterium exchange in different MHC I domains and associated β2-microglobulin across various allotypes.

Main Results:

• Significant differences in hydrogen-deuterium exchange were observed between peptide-loaded and peptide-receptive MHC I molecules.
• UV-induced peptide hydrolysis led to increased deuterium exchange in the peptide-binding domain and other regions, indicating long-range conformational changes.
• Allotype-specific differences in hydrogen-deuterium exchange patterns were detected, supporting the role of MHC I plasticity in peptide selection.

Conclusions:

• MHC I molecules possess inherent dynamic conformational plasticity that is modulated by peptide binding.
• This conformational plasticity is a key factor in the selective binding and presentation of peptides, influencing immune recognition.
• Understanding MHC I dynamics offers potential for developing novel immune-modulatory therapies.