title: Peptide modulation of class I major histocompatibility complex protein molecular flexibility and the implications for immune recognition.
abstract: T cells use the αβ T cell receptor (TCR) to recognize antigenic peptides presented by class I major histocompatibility complex proteins (pMHCs) on the surfaces of antigen-presenting cells. Flexibility in both TCRs and peptides plays an important role in antigen recognition and discrimination. Less clear is the role of flexibility in the MHC protein; although recent observations have indicated that mobility in the MHC can impact TCR recognition in a peptide-dependent fashion, the extent of this behavior is unknown. Here, using hydrogen/deuterium exchange, fluorescence anisotropy, and structural analyses, we show that the flexibility of the peptide binding groove of the class I MHC protein HLA-A*0201 varies significantly with different peptides. The variations extend throughout the binding groove, impacting regions contacted by TCRs as well as other activating and inhibitory receptors of the immune system. Our results are consistent with statistical mechanical models of protein structure and dynamics, in which the binding of different peptides alters the populations and exchange kinetics of substates in the MHC conformational ensemble. Altered MHC flexibility will influence receptor engagement, impacting conformational adaptations, entropic penalties associated with receptor recognition, and the populations of binding-competent states. Our results highlight a previously unrecognized aspect of the "altered self" mechanism of immune recognition and have implications for specificity, cross-reactivity, and antigenicity in cellular immunity.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Hawse
authors.forename: Brian E
authors.initials: BE
authors.lastname: Gloor
authors.forename: Cory M
authors.initials: CM
authors.lastname: Ayres
authors.forename: Kevin
authors.initials: K
authors.lastname: Kho
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nuter
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
mesh_terms: D041961:Deuterium Exchange Measurement; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D018448:Models, Immunological; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000276:immunology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology
chemical_list: C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: Fluorescence; Major Histocompatibility complex (MHC); Mass Spectrometry (MS); Peptides; Protein Dynamics