6mf8

Publication Abstract from PubMed

Initial molecular details of cellular activation following alphabetaT cell antigen receptor (TCR) ligation by peptide-major histocompatibility complexes (pMHC) remain unexplored. We determined the nuclear magnetic resonance (NMR) structure of the TCRalpha subunit transmembrane (TM) domain revealing a bipartite helix whose segmentation fosters dynamic movement. Positively charged TM residues Arg251 and Lys256 project from opposite faces of the helix, with Lys256 controlling immersion depth. Their modification caused stepwise reduction in TCR associations with CD3zetazeta homodimers and CD3epsilongamma plus CD3epsilondelta heterodimers, respectively, leading to an activated transcriptome. Optical tweezers revealed that Arg251 and Lys256 mutations altered alphabetaTCR-pMHC bond lifetimes, while mutations within interacting TCRalpha connecting peptide and CD3delta CxxC motif juxtamembrane elements selectively attenuated signal transduction. Our findings suggest that mechanical forces applied during pMHC ligation initiate T cell activation via a dissociative mechanism, shifting disposition of those basic sidechains to rearrange TCR complex membrane topology and weaken TCRalphabeta and CD3 associations.

The T Cell Antigen Receptor alpha Transmembrane Domain Coordinates Triggering through Regulation of Bilayer Immersion and CD3 Subunit Associations.,Brazin KN, Mallis RJ, Boeszoermenyi A, Feng Y, Yoshizawa A, Reche PA, Kaur P, Bi K, Hussey RE, Duke-Cohan JS, Song L, Wagner G, Arthanari H, Lang MJ, Reinherz EL Immunity. 2018 Nov 20;49(5):829-841.e6. doi: 10.1016/j.immuni.2018.09.007. Epub, 2018 Oct 30. PMID:30389415^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.