posters 5th Asia-Pacific NMR Symposium 2013

Peptide recognition and stabilization mechanism of Human Leukocyte Antigen B*35:01 (#228)

Saeko Yanaka 1 , Takamasa Ueno 2 , Yi Shi 3 4 , Jianxun Qi 3 4 , George F Gao 3 4 , Kouhei Tsumoto 5 6 7 , Kenji Sugase 1
  1. Suntory Foundation for Life Science, Mishima, Osaka, Japan
  2. Center for AIDS Research, Kumamoto University, Kumamoto
  3. Research Network of Immunity and Health, Beijing Institute of Life Science, Chinese Academy of Sciences, Beijing
  4. CAS Key Labolatory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing
  5. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo
  6. Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Tokyo
  7. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo

In an immune-mediated control of pathogens, human leukocyte antigen (HLA) class I presents various antigenic peptides to cytotoxic T lymphocyte (CTL). The stability and long-lived presentation of the peptide-HLA complex (pHLA), important for efficient antigen-specific CTL activation, highly depends on bound peptides. Crystal structures of pHLA, however, are very similar to each other irrespective of the peptides. Thus, the inherent determinant for pHLA stabilization and peptide recognition remains elusive. In this study, we have examined the mechanism by which HLA-B*35:01 recognizes various peptides and stabilizes the complex by elucidating its conformational dynamics using relaxation dispersion NMR spectroscopy. HLA-B*35:01 is one of the most investigated HLAs in the light of the relationship between antigenic peptide and CTL activity. The NMR experiments of three pHLAs with different peptides showed that the peptide binding-domain in pHLAs fluctuates between the major and minor conformation in solution, and that the transition to the minor conformation is accompanied with a negative change of heat capacity ΔCp, indicating the more dehydrated well-packed conformation of the minor state. Interestingly, the minor populations detected by the relaxation dispersion experiments correlated well with their CTL activation durations. Taken all results together, we revealed that pHLA loosely recognizes various peptides with a highly identical conformation, and transiently forms a more dehydrated minor conformation in which the peptide is more tightly bound, resulting in circumvention of pHLA disintegration. Here, we propose this dynamic recognition-stabilization mechanism as “the transient induced fit model”.