title: Dynamics of free versus complexed β2-microglobulin and the evolution of interfaces in MHC class I molecules.
abstract: In major histocompatibility complex (MHC) class I molecules, monomorphic β(2)-microglobulin (β(2)m) is non-covalently bound to a heavy chain (HC) exhibiting a variable degree of polymorphism. β(2)M can stabilize a wide variety of complexes ranging from classical peptide binding to nonclassical lipid presenting MHC class I molecules as well as to MHC class I-like molecules that do not bind small ligands. Here we aim to assess the dynamics of individual regions in free as well as complexed β(2)m and to understand the evolution of the interfaces between β(2)m and different HC. Using human β(2)m and the HLA-B*27:09 complex as a model system, a comparison of free and HC-bound β(2)m by nuclear magnetic resonance spectroscopy was initially carried out. Although some regions retain their flexibility also after complex formation, these studies reveal that most parts of β(2)m gain rigidity upon binding to the HC. Sequence analyses demonstrate that some of the residues exhibiting flexibility participate in evolutionarily conserved β(2)m-HC contacts which are detectable in diverse vertebrate species or characterize a particular group of MHC class I complexes such as peptide- or lipid-binding molecules. Therefore, the spectroscopic experiments and the interface analyses demonstrate that β(2)m fulfills its role of interacting with diverse MHC class I HC as well as effector cell receptors not only by engaging in conserved intermolecular contacts but also by falling back upon key interface residues that exhibit a high degree of flexibility.
authors.affiliation: Institut für Immungenetik, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, Germany.
authors.forename: Chee-Seng
authors.initials: CS
authors.lastname: Hee
authors.forename: Monika
authors.initials: M
authors.lastname: Beerbaum
authors.forename: Bernhard
authors.initials: B
authors.lastname: Loll
authors.forename: Martin
authors.initials: M
authors.lastname: Ballaschk
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D000949:Histocompatibility Antigens Class II / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014714:Vertebrates / Q000235:genetics; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015796:HLA-B27 Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D001613:beta 2-Microglobulin