Journal Article

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

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

2017

Overview

The molecular mechanism through which the interaction of a clonotypic αβ 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 β-chain dynamics reveals significant chemical shift effects in sites removed from the MHC-binding site. Remodelling of electrostatic interactions near the Cβ 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. Binding of T cell receptors (TCR) to peptide-loaded major histocompatibility complexes (p/MHC) leads to T-cell activation. Here the authors give structural insights into T-cell signalling and show that p/MHC binding induces conformational changes at the membrane-proximal site of the TCR.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/31 / 140/131 / 631/250/516 / 631/45/535/878/1263 / 82/103 / 82/6 / 82/80 / Humanities and Social Sciences / multidisciplinary / Science / Science (multidisciplinary)