Selector function of MHC I molecules is determined by protein plasticity

Area of Science:

• Immunology
• Molecular Biology
• Computational Biology

Background:

• Major histocompatibility complex class I (MHC I) molecules present peptides on cell surfaces, initiating immune responses.
• The precise mechanisms by which MHC I rapidly selects high-affinity peptides from a vast repertoire remain largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying MHC I peptide selection.
• To investigate the role of protein plasticity and the co-factor tapasin in MHC I function.

Main Methods:

• Developed computational systems models for HLA-B*44:02 and HLA-B*44:05 molecules.
• Utilized in vivo biochemical data and molecular dynamics simulations.
• Experimentally altered MHC I plasticity via point mutation and assessed in vivo function.

Main Results:

• Inferred the significance of a conformational intermediate in MHC I peptide selection.
• Demonstrated a correlation between MHC I peptide selector function and protein plasticity.
• Showed that altering MHC I plasticity with a mutation predictably changed its in vivo selector function.
• Identified tapasin as a modulator of MHC I plasticity through allosteric coupling.

Conclusions:

• MHC I peptide selection is strongly influenced by protein plasticity.
• Tapasin enhances MHC I peptide selection by allosterically modulating protein plasticity.
• Understanding these mechanisms is vital for adaptive immunity and therapeutic interventions.