Journal Article

Dynamics of free versus complexed β2-microglobulin and the evolution of interfaces in MHC class I molecules

Schmieder, Peter, Ballaschk, Martin, Ziegler, Andreas, Uchanska-Ziegler, Barbara, Beerbaum, Monika, Loll, Bernhard, Hee, Chee-Seng

2013

Overview

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.

• Publisher: Springer-Verlag
• Subject: Allergology / Amino Acid Sequence / Animals / beta 2-Microglobulin - chemistry / beta 2-Microglobulin - genetics / beta 2-Microglobulin - metabolism / Biomedical and Life Sciences / Biomedicine / Cell Biology / Conserved Sequence / Evolution, Molecular / Gene Function / Genes, MHC Class I / Genes, MHC Class II / Histocompatibility Antigens Class I - chemistry / Histocompatibility Antigens Class II - chemistry / HLA-B27 Antigen - chemistry / HLA-B27 Antigen - metabolism / Human Genetics / Humans / Immunology / Magnetic Resonance Spectroscopy / Models, Molecular / Molecular Sequence Data / Original Paper / Protein Binding / Protein Conformation / Protein Interaction Mapping / Protein Structure, Tertiary / Receptors, Antigen, T-Cell - chemistry / Receptors, Antigen, T-Cell - genetics / Sequence Alignment / Sequence Homology, Amino Acid / Species Specificity / Vertebrates - genetics