Structural evolution of polymorphic class I HLA alleles, designating HLA-C with uncertain assemblies.

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• Major histocompatibility complex (MHC) class I molecules, including human leukocyte antigen (HLA) alleles, are critical for adaptive immunity and T-cell recognition.
• Their high polymorphism and structural variations in ectodomains and transmembrane regions present challenges for understanding antigen presentation.
• The precise structural landscape and evolutionary diversity of HLA molecules remain incompletely understood.

Purpose of the Study:

• To investigate conserved structural features across family-wide HLA-A, HLA-B, and HLA-C alleles.
• To impute full-length HLA structures and analyze their variance.
• To correlate structural properties with peptide-binding affinity and potential for T-cell interactions.

Main Methods:

• Examination of family-wide conserved HLA-A, HLA-B, and HLA-C alleles.
• Imputation of full-length HLA structures using sequence data.
• Analysis of amino acid conservation, secondary structures, and internal energies.
• Comparison of structural properties across different HLA allelic families.

Main Results:

• Conserved amino acids in HLA molecules are located near C-terminus antigen binding sites.
• HLA-A alleles exhibit higher affinity structures compared to HLA-B and HLA-C.
• Specific allelic families (HLA-A*02, HLA-B*57, HLA-C*03) display well-defined secondary structures.
• HLA-C alleles show structural deficiencies and lower internal contact energy.
• Non-expressed alleles possess poor secondary structures, indicating reduced peptide presentation potential.

Conclusions:

• Cell-surface HLA molecule structures are optimized for peptide binding and selectivity.
• Structural insights into HLA allelic families reveal distinct properties influencing immune response.
• Quantification of internal energies can assess HLA expression levels.
• Understanding common HLA structural assemblies can inform peptide-based vaccine development for immunocompromised individuals.