title: Antigen ligation triggers a conformational change within the constant domain of the alphabeta T cell receptor.
abstract: Ligation of the alphabeta T cell receptor (TCR) by a specific peptide-loaded major histocompatibility complex (pMHC) molecule initiates T cell signaling via the CD3 complex. However, the initial events that link antigen recognition to T cell signal transduction remain unclear. Here we show, via fluorescence-based experiments and structural analyses, that MHC-restricted antigen recognition by the alphabeta TCR results in a specific conformational change confined to the A-B loop within the alpha chain of the constant domain (Calpha). The apparent affinity constant of this A-B loop movement mirrored that of alphabeta TCR-pMHC ligation and was observed in two alphabeta TCRs with distinct pMHC specificities. The Ag-induced A-B loop conformational change could be inhibited by fixing the juxtapositioning of the constant domains and was shown to be reversible upon pMHC disassociation. Notably, the loop movement within the Calpha domain, although specific for an agonist pMHC ligand, was not observed with a pMHC antagonist. Moreover, mutagenesis of residues within the A-B loop impaired T cell signaling in an in vitro system of antigen-specific TCR stimulation. Collectively, our findings provide a basis for the earliest molecular events that underlie Ag-induced T cell triggering.
authors.affiliation: Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Chen
authors.forename: Craig S
authors.initials: CS
authors.lastname: Clements
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Ely
authors.forename: Simon R
authors.initials: SR
authors.lastname: Bushell
authors.forename: Julian P
authors.initials: JP
authors.lastname: Vivian
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: Siew Siew
authors.initials: SS
authors.lastname: Pang
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Dunstone
authors.forename: Yu Chih
authors.initials: YC
authors.lastname: Liu
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Macdonald
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Perugini
authors.forename: Matthew C J
authors.initials: MC
authors.lastname: Wilce
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D000818:Animals; D000941:Antigens / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta