Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3epsilon.
The CD3epsilon subunit of the T cell receptor (TCR) complex undergoes a conformational change upon ligand binding that is thought to be important for the activation of T cells. To study this process, we built a molecular dynamics model of the transmission of the conformational change within the ectodomains of CD3. The model showed that the CD3 dimers underwent a stiffening effect that was funneled to the base of the CD3epsilon subunit. Mutation of two relevant amino acid residues blocked transmission of the conformational change and the differentiation and activation of T cells. Furthermore, this inhibition occurred even in the presence of excess endogenous CD3epsilon subunits. These results emphasize the importance of the conformational change in CD3epsilon for the activation of T cells and suggest the existence of unforeseen cooperativity between TCR complexes.
Martínez-Martín
Nuria
N
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain.
Risueño
Ruth M
RM
Morreale
Antonio
A
Zaldívar
Irene
I
Fernández-Arenas
Elena
E
Herranz
Fernando
F
Ortiz
Angel R
AR
Alarcón
Balbino
B
D000818:Animals; D017252:CD3 Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism
D017252:CD3 Complex; C485468:Cd3e protein, mouse; D050505:Mutant Proteins; D011948:Receptors, Antigen, T-Cell