Cooperativity Between T Cell Receptor Complexes Revealed by Conformational Mutants of CD3

Nuria Martínez-Martín^1*, Ruth M. Risueño^1*, Antonio Morreale^2*, Irene Zaldívar¹, Elena Fernández-Arenas¹, Fernando Herranz², Angel R. Ortiz², and Balbino Alarcón¹

¹ Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain.
² Bioinformatics Unit, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain.

Deceased 5 May 2008.

Abstract: The CD3 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 CD3 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 CD3 subunits. These results emphasize the importance of the conformational change in CD3 for the activation of T cells and suggest the existence of unforeseen cooperativity between TCR complexes.

To whom correspondence should be addressed. E-mail: balarcon{at}cbm.uam.es

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