TY - JOUR
T1 - Antigen ligation triggers a conformational change within the constant domain of the alphabeta T cell receptor
AU - Beddoe, Travis Clarke
AU - Chen, Zhenjun
AU - Clements, Craig Steven
AU - Ely, Lauren Kate
AU - Bushell, Simon Robert
AU - Vivian, Julian P
AU - Kjer-Nielsen, Lars
AU - Pang, Siew Siew
AU - Dunstone, Michelle Anne
AU - Liu, Yu Chih
AU - Macdonald, Whitney Alison
AU - Perugini, Matthew Anthony
AU - Wilce, Matthew Charles James
AU - Burrows, Scott R
AU - Purcell, Anthony Wayne
AU - Tiganis, Tony
AU - Bottomley, Stephen Paul
AU - McCluskey, James
AU - Rossjohn, Jamie
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - http://www.sciencedirect.com/science/article/pii/S1074761309001952
U2 - 10.1016/j.immuni.2009.03.018
DO - 10.1016/j.immuni.2009.03.018
M3 - Article
VL - 30
SP - 777
EP - 788
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 6
ER -