Abstract
Mechanotransduction is a basis for receptor signaling in many biological systems. Recent data based upon optical tweezer experiments suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into biochemical signals upon specific peptide-MHC complex (pMHC) ligation. Tangential force applied along the pseudo-twofold symmetry axis of the TCR complex post-ligation results in the αβ heterodimer exerting torque on the CD3 heterodimers as a consequence of molecular movement at the T cell–APC interface. Accompanying TCR quaternary change likely fosters signaling via the lipid bilayer predicated on the magnitude and direction of the TCR–pMHC force. TCR glycans may modulate quaternary change, thereby altering signaling outcome as might the redox state of the CxxC motifs located proximal to the TM segments in the heterodimeric CD3 subunits. Predicted alterations in TCR TM segments and surrounding lipid will convert ectodomain ligation into the earliest intracellular signaling events.
Highlights
THE TCR STRUCTURE: OVERVIEW The αβ TCR is a multimeric transmembrane complex composed of a disulfide-linked antigen binding clonotypic heterodimer in non-covalent association with the signal-transducing CD3 subunits (CD3εγ, CD3εδ, and CD3ζζ)
The interaction between an αβ TCR heterodimer on the T cell and a peptide-MHC complex (pMHC) ligand on an antigen-presenting cell (APC) initiates a cascade of downstream signaling events. These events are transmitted via the immunoreceptor tyrosine-based activation motif (ITAM) elements in the cytoplasmic tails of the associated CD3 subunits, whose lengths are substantial relative to those of the TCR α and β tails (Reth, 1989; Letourneur and Klausner, 1992; Acuto et al, 2008; van der Merwe and Dushek, 2011) The various CD3 chains induce distinct patterns of cellular protein tyrosine phosphorylation upon activation to recruit intracellular adaptors and signaling molecules
How recognition of pMHC by a weakly interacting αβ TCR heterodimer on the T cell surface evokes intracellular signaling via the adjacent CD3 components of the TCR complex has remained undefined
Summary
THE TCR STRUCTURE: OVERVIEW The αβ TCR is a multimeric transmembrane complex composed of a disulfide-linked antigen binding clonotypic heterodimer in non-covalent association with the signal-transducing CD3 subunits (CD3εγ, CD3εδ, and CD3ζζ) (reviewed in Rudolph et al, 2006; Smith-Garvin et al, 2009). Structural insights from crystallographic data on the glycosylated N15 TCRαβ heterodimer ectodomain in complex with H57 Fab and the likely position of glycans in both CD3εγ and CD3εδ (Wang et al, 1998) are considered.
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