An allosteric site in the T-cell receptor C beta domain plays a critical signalling role

作者：Natarajan Kannan; McShan Andrew C; Jiang Jiansheng; Kumirov Vlad K; Wang Rui; Zhao Huaying; Schuck Peter; Tilahun Mulualem E; Boyd Lisa F; Ying Jinfa; Bax Ad; Margulies David H^*; Sgourakis Nikolaos G^*

来源：Nature Communications, 2017, 8(1): 15260.

DOI：10.1038/ncomms15260

The molecular mechanism through which the interaction of a clonotypic alpha beta T-cell receptor (TCR) with a peptide-loaded major histocompatibility complex (p/MHC) leads to T-cell activation is not yet fully understood. Here we exploit a high-affinity TCR (B4.2.3) to examine the structural changes that accompany binding to its p/MHC ligand (P18-I10/H2-D-d). In addition to conformational changes in complementarity-determining regions (CDRs) of the TCR seen in comparison of unliganded and bound X-ray structures, NMR characterization of the TCR beta-chain dynamics reveals significant chemical shift effects in sites removed from the MHC-binding site. Remodelling of electrostatic interactions near the C beta H3 helix at the membrane-proximal face of the TCR, a region implicated in interactions with the CD3 co-receptor, suggests a possible role for an allosteric mechanism in TCR signalling. The contribution of these TCR residues to signal transduction is supported by mutagenesis and T-cell functional assays.

• 出版日期2017-5-16