MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Major histocompatibility complex class II (MHC-II) molecules present antigenic peptides to T helper cells, dictating immune responses.
• Polymorphism in the MHC-II genetic locus leads to diverse allotypes, influencing the presented peptide repertoire.
• Human leukocyte antigen (HLA)-DM (DM) facilitates peptide exchange on MHC-II by interacting with dynamic features.

Purpose of the Study:

• To investigate the dynamics of 12 abundant CLIP-bound HLA-DRB1 allotypes.
• To correlate these dynamics with HLA-DM (DM) catalyzed peptide exchange.
• To understand how MHC-II allotype variations contribute to autoimmune diseases.

Main Methods:

• Investigated 12 CLIP-bound HLA-DRB1 allotypes.
• Analyzed peptide exchange rates and thermodynamic stability.
• Correlated molecular dynamics with DM catalysis.

Main Results:

• Peptide exchange rates for diverse MHC-II allotypes fall within a range that maintains DM responsiveness, despite varying thermodynamic stability.
• A conserved DM-susceptible conformation exists across MHC-II molecules.
• Allosteric coupling between polymorphic sites influences dynamic states and DM catalysis.

Conclusions:

• Intrinsic dynamic features of peptide-MHC-II complexes are crucial for DM catalysis.
• These dynamics may explain the association of specific MHC-II allotypes with autoimmune diseases like rheumatoid arthritis.