Molecular mechanisms for the assembly of the T cell receptor-CD3 complex.
The T cell receptor (TCR)-CD3 complex represents on of the most intricate membrane receptor structures since it is built from six distinct chains. This complexity led to a number of different proposals for the arrangement of the receptor subunits, its stoichiometry and the mechanisms responsible for receptor triggering. Early work had demonstrated that basic and acidic transmembrane (TM) residues were involved in the assembly but the molecular arrangement could not be deduced due to the complexity of the receptor. Using a novel method for the isolation of intact radiolabeled protein complexes, we demonstrated that the complex assembled in the ER contains only a single TCRalphabeta heterodimer and one copy of each of the CD3deltaepsilon, CD3gammaepsilon and zeta-zeta signaling dimers. Surprisingly, assembly of each of the three signaling dimers with TCR was dependent on one of the three basic TCR TM residues as well as both acidic residues located in the TM domains of the interacting signaling dimer. Each assembly step thus results in the formation of a three-helix interface in the membrane that involves one basic and two acidic TM residues, and this arrangement effectively shields these ionizable residues at protein-protein interfaces from the lipid. Since proteins whose TM domains have exposed ionizable residues are not stably integrated into the lipid bilayer, assembly based on shielding of ionizable residues permits full equilibration of the receptor into the lipid bilayer and prevents degradation. Assembly, export of intact receptor complexes and degradation of unassembled components thus rely on the same organizing principle.
Call
Matthew E
ME
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Wucherpfennig
Kai W
KW
D000595:Amino Acid Sequence; D000818:Animals; D017252:CD3 Complex / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000096:biosynthesis* / Q000737:chemistry / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry
D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; C121704:CD3 antigen, zeta chain; C472562:CD3delta antigen; C485468:Cd3e protein, mouse; D046911:Macromolecular Substances; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta