title: Natural MHC class I polymorphism controls the pathway of peptide dissociation from HLA-B27 complexes.
abstract: Analysis of antigen dissociation provides insight into peptide presentation modes of folded human leukocyte antigen (HLA) molecules, which consist of a heavy chain, beta2-microglobulin (beta2m), and an antigenic peptide. Here we have monitored peptide-HLA interactions and peptide dissociation kinetics of two HLA-B27 subtypes by fluorescence depolarization techniques. A single natural amino-acid substitution distinguishes the HLA-B*2705 subtype that is associated with the autoimmune disease ankylosing spondylitis from the non-disease-associated HLA-B*2709 subtype. Peptides with C-terminal Arg or Lys represent 27% of the natural B*2705 ligands. Our results show that dissociation of a model peptide with a C-terminal Lys (GRFAAAIAK) follows a two-step mechanism. Final peptide release occurs in the second step for both HLA-B27 subtypes. However, thermodynamics and kinetics of peptide-HLA interactions reveal different molecular mechanisms underlying the first step, as indicated by different activation energies of 95+/-8 kJ/mol (HLA-B*2705) and 150+/-10 kJ/mol (HLA-B*2709). In HLA-B*2709, partial peptide dissociation probably precedes fast final peptide release, while in HLA-B*2705 an allosteric mechanism based on long-range interactions between beta2m and the peptide binding groove controls the first step. The resulting peptide presentation mode lasts for days at physiological temperature, and determines the peptide-HLA-B*2705 conformation, which is recognized by cellular ligands such as T-cell receptors.
authors.affiliation: Physics Department, Freie Universität Berlin, Berlin, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Winkler
authors.forename: Anja
authors.initials: A
authors.lastname: Winter
authors.forename: Christine
authors.initials: C
authors.lastname: Rueckert
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
authors.forename: Ulrike
authors.initials: U
authors.lastname: Alexiev
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D005805:Genes, MHC Class I; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000648:ultrastructure*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D015796:HLA-B27 Antigen; D010455:Peptides