title: A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ.
abstract: 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.
authors.affiliation: Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA.
authors.forename: Caleb R
authors.initials: CR
authors.lastname: Glassman
authors.affiliation: Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA; The Arizona Center on Aging, The University of Arizona College of Medicine, Tucson, AZ 85724, USA.
authors.forename: Neha R
authors.initials: NR
authors.lastname: Deshpande
authors.affiliation: Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA.
authors.forename: Hemant B
authors.initials: HB
authors.lastname: Badgandi
authors.affiliation: Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Parrish
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.
authors.forename: Chayasith
authors.initials: C
authors.lastname: Uttamapinant
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Stawski
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.
authors.forename: Alice Y
authors.initials: AY
authors.lastname: Ting
authors.affiliation: Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA; The Arizona Center on Aging, The University of Arizona College of Medicine, Tucson, AZ 85724, USA; The BIO-5 Institute, The University of Arizona College of Medicine, Tucson, AZ 85724, USA. Electronic address: mkuhns@u.arizona.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kuhns
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas; D040542:Mechanotransduction, Cellular; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D015202:Protein Engineering; D055503:Protein Multimerization / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D020239:Receptor Cross-Talk; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D046912:Multiprotein Complexes; D011948:Receptors, Antigen, T-Cell