Sequence-structure-function relationships in class I MHC: A local frustration perspective

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• Class I Major Histocompatibility Complex (MHC) presents antigenic peptides to T-cell Receptors (TCRs) and Killer-cell Immunglobulin-like Receptors (KIRs).
• Human Leukocyte Antigen (HLA) I is the most polymorphic human protein, with over 10,000 alleles, impacting peptide binding and immune recognition.
• Despite extensive allelic diversity, the three-dimensional structure of HLA Class I remains largely conserved.

Purpose of the Study:

• To establish a framework linking polymorphism, structure, and function in human MHC Class I.
• To analyze local frustration in peptide-MHC (pMHC) homology models across numerous HLA I alleles.
• To understand how sequence variations and structural features influence HLA-peptide-TCR/KIR interactions.

Main Methods:

• Local frustration analysis was performed on homology models of pMHC.
• Models covered 1436 distinct HLA Class I alleles.
• Analysis focused on identifying conserved and frustrated residues within the HLA structure and their relation to interaction sites.

Main Results:

• Minimally-frustrated and conserved residues in the peptide-binding groove suggest structural stability despite polymorphism.
• High frustration patches on HLA helices are located near or within interaction sites for TCR, KIR, and tapasin (Peptide Loading Complex).
• Peptide ligands primarily stabilize the F-pocket of the HLA binding groove.

Conclusions:

• HLA Class I fold is conserved due to minimally-frustrated residues in the peptide-binding groove.
• Frustration analysis effectively maps functionally important regions involved in protein-protein interactions.
• Understanding these relationships is crucial for deciphering immune recognition mechanisms and developing targeted therapies.