Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation.
Cell Rep
; 36(2): 109375, 2021 07 13.
Article
in En
| MEDLINE
| ID: mdl-34260912
ABSTRACT
The mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRß or CD3ζ that augment peptide T cell antigen receptor (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and molecular dynamics simulation, we demonstrate that the gain-of-function mutations loosen the interaction between TCRαß and CD3ζ. Similar to the activating mutations, pMHC binding reduces TCRαß cohesion with CD3ζ. This event occurs prior to CD3ζ phosphorylation and at 0°C. Moreover, we demonstrate that soluble monovalent pMHC alone induces signaling and reduces TCRαß cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαß to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to license CD3ζ phosphorylation and initiate signal propagation.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Antigen, T-Cell
/
Signal Transduction
Limits:
Humans
Language:
En
Journal:
Cell Rep
Year:
2021
Document type:
Article
Affiliation country:
United kingdom