Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 48, Pages 36977-36984Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M607164200
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- NIAID NIH HHS [R01 AI054520] Funding Source: Medline
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Assembly of the T cell receptor (TCR) with its dimeric signaling modules, CD3 delta epsilon, CD3 gamma epsilon, and zeta zeta, is organized by transmembrane (TM) interactions. Each of the three assembly steps requires formation of a three-helix interface involving one particular basic TCR TM residue and two acidic TM residues of the respective signaling dimer. The extracellular domains of CD3 delta epsilon and CD3 gamma epsilon contribute to assembly, but TCR interaction sites on CD3 dimers have not been defined. The structures of the extracellular domains of CD3 delta epsilon and CD3 gamma epsilon demonstrated parallel beta-strands ending at the first cysteine in the CXXCXEXXX motif present in the stalk segment of each CD3 chain. Mutation of the membrane-proximal cysteines impaired assembly of either CD3 dimer with TCR, and little complex was isolated when all four membrane-proximal cysteines were mutated to alanine. These mutations had, however, no discernable effect on CD3 delta epsilon or CD3 gamma epsilon dimerization. CD3 delta epsilon assembled with a TCR alpha mutant that lacked both immunoglobulin domains, but shortening of the TCR alpha connecting peptide reduced assembly, consistent with membrane-proximal TCR alpha-CD3 delta epsilon interactions. Chelation of divalent cations did not affect assembly, indicating that coordination of a cation by the tetracysteine motif was not required. The membrane-proximal cysteines were within close proximity but only formed covalent CD3 dimers when one cysteine was mutated. The four cysteines may thus form two intrachain disulfide bonds integral to the secondary structure of CD3 stalk regions. The three-chain interaction theme first established for the TM domains thus extends into the membrane-proximal domains of TCR alpha-CD3 delta epsilon and TCR alpha-CD3 delta epsilon.
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