Immunity (Cambridge, Mass.), 2018-11, Vol.49 (5), p.829-841.e6
2018
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- Autor(en) / Beteiligte
- Titel
- The T Cell Antigen Receptor α Transmembrane Domain Coordinates Triggering through Regulation of Bilayer Immersion and CD3 Subunit Associations
- Ist Teil von
- Immunity (Cambridge, Mass.), 2018-11, Vol.49 (5), p.829-841.e6
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2018
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Initial molecular details of cellular activation following αβT cell antigen receptor (TCR) ligation by peptide-major histocompatibility complexes (pMHC) remain unexplored. We determined the nuclear magnetic resonance (NMR) structure of the TCRα 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 CD3ζζ homodimers and CD3εγ plus CD3εδ heterodimers, respectively, leading to an activated transcriptome. Optical tweezers revealed that Arg251 and Lys256 mutations altered αβTCR-pMHC bond lifetimes, while mutations within interacting TCRα connecting peptide and CD3δ 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 TCRαβ and CD3 associations. [Display omitted] •The TCRα transmembrane (TM) domain is a bipartite helix separated by a dynamic hinge•Lys256 controls the TCRαTM depth and CD3 homo- and heterodimer associations•The TCRα- and CD3δ-juxtamembrane elements mediate a specific TCRα-CD3δ interaction•Key residues within TCRαTM or juxtamembrane domains govern αβTCR mechanotransduction While TCR triggering is critical for adaptive immunity, how bioforces accompanying ligand binding transduce signals through the cell membrane is unknown. Brazin et al. define dynamic structural movements within the TCRα transmembrane domain linked to fundamental TCR complex mechanobiology, including subunit topological rearrangements that foster dissociation of CD3 dimers and cell activation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-7613eISSN: 1097-4180DOI: 10.1016/j.immuni.2018.09.007Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6249037
- Format
- –
- Schlagworte
- Amino Acid Sequence, Amino acids, Antigens, Biomarkers, CAR-T, CD3 antigen, CD3 Complex - chemistry, CD3 Complex - metabolism, Cell activation, Cell Membrane - metabolism, Conserved Sequence, EPR, Gene expression, Gene Expression Profiling, Histocompatibility, Hypotheses, Image processing, Immersion, Immunotherapy, Lymphocytes, Lymphocytes T, Mammals, mechanoreceptor, Models, Molecular, Mutation, NMR, Nuclear magnetic resonance, optical tweezers, Peptides, Protein Binding, Protein Conformation, Protein Domains, Protein Multimerization, Receptors, Antigen, T-Cell, alpha-beta - chemistry, Receptors, Antigen, T-Cell, alpha-beta - genetics, Receptors, Antigen, T-Cell, alpha-beta - metabolism, Segmentation, Signal Transduction, Spectrum analysis, Submerging, T cell activation, T cell receptors, TCR, Topology, Transcriptome, transmembrane domain, Transmembrane domains, Vertebrates