title: Peptide-dependent conformational fluctuation determines the stability of the human leukocyte antigen class I complex.
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.
authors.affiliation: From the Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 277-8562, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Yanaka
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Research Network of Immunity and Health, Beijing Institute of Life Science, Chinese Academy of Sciences, Beijing 100101, China, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Research Network of Immunity and Health, Beijing Institute of Life Science, Chinese Academy of Sciences, Beijing 100101, China, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Research Network of Immunity and Health, Beijing Institute of Life Science, Chinese Academy of Sciences, Beijing 100101, China, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: From the Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 277-8562, Japan, Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 108-8693, Japan, Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Tokyo 108-8693, Japan, and tsumoto@k.u-tokyo.ac.jp.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
authors.affiliation: Bioorganic Research Institute, Suntory Foundation for Life Sciences, Osaka 618-8503, Japan sugase@sunbor.or.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugase
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides
keywords: Major Histocompatibility Complex (MHC); Nuclear Magnetic Resonance (NMR); Protein Dynamic; Protein Stability; Thermodynamics