Cutting edge: Evidence for a dynamically driven T cell signaling mechanism
Department of Biochemistry and Molecular Pharmacology; Program in Bioinformatics and Integrative Biology
Medical Subject Headings
Animals; Computational Biology; HLA-A2 Antigen; Humans; Lymphocyte Activation; Peptide Fragments; Protein Structure, Quaternary; Receptors, Antigen, T-Cell; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Surface Plasmon Resonance; T-Lymphocytes; Urokinase-Type Plasminogen Activator
Bioinformatics | Computational Biology | Immunology and Infectious Disease
T cells use the alphabeta TCR to bind peptides presented by MHC proteins (pMHC) on APCs. Formation of a TCR-pMHC complex initiates T cell signaling via a poorly understood process, potentially involving changes in oligomeric state, altered interactions with CD3 subunits, and mechanical stress. These mechanisms could be facilitated by binding-induced changes in the TCR, but the nature and extent of any such alterations are unclear. Using hydrogen/deuterium exchange, we demonstrate that ligation globally rigidifies the TCR, which via entropic and packing effects will promote associations with neighboring proteins and enhance the stability of existing complexes. TCR regions implicated in lateral associations and signaling are particularly affected. Computational modeling demonstrated a high degree of dynamic coupling between the TCR constant and variable domains that is dampened upon ligation. These results raise the possibility that TCR triggering could involve a dynamically driven, allosteric mechanism.
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Citation: J Immunol. 2012 Jun 15;188(12):5819-23. doi: 10.4049/jimmunol.1200952. Link to article on publisher's site
Hawse, William F.; Champion, Matthew M.; Joyce, Michelle V.; Hellman, Lance M.; Hossain, Moushumi; Ryan, Veronica; Pierce, Brian G.; Weng, Zhiping; and Baker, Brian M., "Cutting edge: Evidence for a dynamically driven T cell signaling mechanism" (2012). Program in Bioinformatics and Integrative Biology Publications and Presentations. 13.