Abstract
In immune-mediated control of pathogens, human leukocyte antigen (HLA) class I presents various antigenic peptides to CD8(+) T-cells. Long-lived peptide presentation is important for efficient antigen-specific T-cell activation. Presentation time depends on the peptide sequence and the stability of the peptide-HLA complex (pHLA). However, the determinant of peptide-dependent pHLA stability remains elusive. Here, to reveal the pHLA stabilization mechanism, we examined the crystal structures of an HLA class I allomorph in complex with HIV-derived peptides and evaluated site-specific conformational fluctuations using NMR. Although the crystal structures of various pHLAs were almost identical independent of the peptides, fluctuation analyses identified a peptide-dependent minor state that would be more tightly packed toward the peptide. The minor population correlated well with the thermostability and cell surface presentation of pHLA, indicating that this newly identified minor state is important for stabilizing the pHLA and facilitating T-cell recognition.
Highlights
The stable presentation of human leukocyte antigen (HLA) is necessary for effective T-cell activity in infectious diseases
The interaction mode between the peptide-HLA complex (pHLA) and T-cell receptors (TCRs) is a key factor in determining the potency of T-cell responses [17, 18], these results suggest that pHLA stability itself has a significant impact on the mounting of efficient T-cell responses
The structure was compared with previously determined crystal structures of HLA-B*35:01 (Table 2), especially HLA/VY8, as HLA/VY8 is more stable than HLA/ RY11 despite the similar sequences of the bound peptides
Summary
The stable presentation of HLA is necessary for effective T-cell activity in infectious diseases. Results: Conformational fluctuation analysis revealed a minor state of HLA. Conclusion: The minor state avoids the disintegration of HLA by tightly packing toward the peptide. The minor population correlates with the elongated presentation of HLA on the cell surface. To reveal the pHLA stabilization mechanism, we examined the crystal structures of an HLA class I allomorph in complex with HIVderived peptides and evaluated site-specific conformational fluctuations using NMR. The crystal structures of various pHLAs were almost identical independent of the peptides, fluctuation analyses identified a peptide-dependent minor state that would be more tightly packed toward the peptide. The minor population correlated well with the thermostability and cell surface presentation of pHLA, indicating that this newly identified minor state is important for stabilizing the pHLA and facilitating T-cell recognition
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