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Peptide cargo tunes a network of correlated motions in human leucocyte antigens.

ABSTRACT: Most biomolecular interactions are typically thought to increase the (local) rigidity of a complex, for example, in drug-target binding. However, detailed analysis of specific biomolecular complexes can reveal a more subtle interplay between binding and rigidity. Here, we focussed on the human leucocyte antigen (HLA), which plays a crucial role in the adaptive immune system by presenting peptides for recognition by the αβ T-cell receptor (TCR). The role that the peptide plays in tuning HLA flexibility during TCR recognition is potentially crucial in determining the functional outcome of an immune response, with obvious relevance to the growing list of immunotherapies that target the T-cell compartment. We have applied high-pressure/temperature perturbation experiments, combined with molecular dynamics simulations, to explore the drivers that affect molecular flexibility for a series of different peptide-HLA complexes. We find that different peptide sequences affect peptide-HLA flexibility in different ways, with the peptide cargo tuning a network of correlated motions throughout the pHLA complex, including in areas remote from the peptide-binding interface, in a manner that could influence T-cell antigen discrimination.

SUBMITTER: Hopkins JR

PROVIDER: S-EPMC8651013 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Peptide cargo tunes a network of correlated motions in human leucocyte antigens.

Hopkins Jade R JR Crean Rory M RM Catici Dragana A M DAM Sewell Andrew K AK Arcus Vickery L VL Van der Kamp Marc W MW Cole David K DK Pudney Christopher R CR

The FEBS journal 20200326 17

Most biomolecular interactions are typically thought to increase the (local) rigidity of a complex, for example, in drug-target binding. However, detailed analysis of specific biomolecular complexes can reveal a more subtle interplay between binding and rigidity. Here, we focussed on the human leucocyte antigen (HLA), which plays a crucial role in the adaptive immune system by presenting peptides for recognition by the αβ T-cell receptor (TCR). The role that the peptide plays in tuning HLA flexi ...[more]

PMID: 32134551

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Project description:Simple Summary Human leucocyte antigens (HLAs) play a crucial role in the immune defense by presenting antigens to T lymphocytes. The particular combination of HLA alleles determines a patient-specific presentation of cell-derived peptide fragments to the patrolling immune cells. Since deregulated protein expression and mutations are hallmarks of cancer, such abnormal peptides can be presented by tumor cells and eventually recognized, and the presenting tumor cells are then killed by T cells. Therefore, the HLA composition might influence the formation and fate of cancer and might differ between tumor patients and healthy individuals. We performed HLA typing of 84 patients with head and neck cancer, and the results were compared to survival. Two of fifty HLA alleles analyzed showed a significantly different frequency compared with the normal population (HLA-A*25 and HLA-C*06). Patients with HLA-C*04 had poorer oncological outcomes, while patients with HLA-A*02 had significantly better survival. Abstract Background: The induction and regulation of immune responses depend on human leucocyte antigen (HLA) molecules that present peptides derived from mutated neoantigens or tumor-associated antigens to cytotoxic T cells. The natural variation of HLA molecules might differ between tumor patients and the normal population. Thus, there might be associations between the frequencies of HLA alleles and the survival of tumor patients. Methods: This issue was studied in a cohort of 84 patients with head and neck squamous cell carcinomas (HNSCCs) of different localizations. The cohort was followed up for more than 10 years. HLA-A/B/C CTS-PCR-SSP typing at 1 field level from blood samples was performed, and the results were correlated with survival. Results: HLA-A*02 was the most prevalent allele in our cohort and was present in 51.1% of patients. The HLA-A*25 and HLA-C*06 alleles exhibited a significantly higher frequency in cancer patients than in the normal population of 174 blood and kidney donors (p = 0.02 and p = 0.01, respectively, Fisher’s exact test). For HLA-C*04, a negative impact on overall survival in univariate analysis (p = 0.045) and a negative, but statistically insignificant effect on survival toward poorer survival in multivariate analysis (HR: 1.82; 95% CI: 0.99–3.34, p = 0.053) were observed. In addition, HLA-A*02 was also beneficial for overall survival and progression-free survival in multivariate analysis (HR 0.54; 95% CI: 0.31–0.92; p = 0.023). Conclusion: HLA-A*02 allele expression might not only predict better survival but might also indicate superior tumor antigen presentation and, thus, help to select patients who could benefit from T-cell-dependent immunotherapies.

Dataset Information

Peptide cargo tunes a network of correlated motions in human leucocyte antigens.

Publications

Peptide cargo tunes a network of correlated motions in human leucocyte antigens.

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