A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ

• Published in: Immunity (Cambridge, Mass.) Mass.), 2015-08, Vol.43 (2), p.227-239
• Main Authors: Lee, Mark S., Glassman, Caleb R., Deshpande, Neha R., Badgandi, Hemant B., Parrish, Heather L., Uttamapinant, Chayasith, Stawski, Philipp S., Ting, Alice Y., Kuhns, Michael S.
• Format: Article
• Language: English
• Subjects: Animals; CD3 Complex - genetics; CD3 Complex - metabolism; Cell Membrane - metabolism; Cytoplasm - metabolism; Humans; Hybridomas; Mechanotransduction, Cellular; Mice; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Protein Conformation; Protein Engineering; Protein Multimerization - genetics; Protein Multimerization - immunology; Protein Structure, Tertiary - genetics; Receptor Cross-Talk; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Signal Transduction - genetics; T-Lymphocytes - immunology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.06.018

The eight-subunit T cell receptor (TCR)-CD3 complex is the primary determinant for T cell fate decisions. Yet how it relays ligand-specific information across the cell membrane for conversion to chemical signals remains unresolved. We hypothesized that TCR engagement triggers a change in the spatial relationship between the associated CD3ζζ subunits at the junction where they emerge from the membrane into the cytoplasm. Using three in situ proximity assays based on ID-PRIME, FRET, and EPOR activity, we determined that the cytosolic juxtamembrane regions of the CD3ζζ subunits are spread apart upon assembly into the TCR-CD3 complex. TCR engagement then triggered their apposition. This mechanical switch resides upstream of the CD3ζζ intracellular motifs that initiate chemical signaling, as well as the polybasic stretches that regulate signal potentiation. These findings provide a framework from which to examine triggering events for activating immune receptors and other complex molecular machines. [Display omitted] •Mechanical coupling of the TCR to CD3ζζ measured at the juxtamembrane region•The CD3ζζ juxtamembrane regions are divaricated in unengaged TCR-CD3 complexes•TCR triggering drives intra-complex apposition of the CD3ζζ juxtamembrane regions•The data provide evidence for a pivot point in the linkage between the TCR and CD3ζζ Despite detailed insights into TCR-pMHC interactions and intracellular signaling, how pMHC-specific information crosses the T cell membrane is unclear. Kuhns and colleagues report that the juxtamembrane regions of the CD3ζζ signaling module are divaricated within the TCR-CD3 complex until TCR engagement triggers their juxtaposition, transferring information across the cell membrane.