Identification of the Docking Site for CD3 on the T Cell Receptor β Chain by Solution NMR.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleIdentification of the Docking Site for CD3 on the T Cell Receptor β Chain by Solution NMR.
Publication TypeJournal Article
Year of Publication2015
AuthorsHe, Y, Rangarajan, S, Kerzic, M, Luo, M, Chen, Y, Wang, Q, Yin, Y, Workman, CJ, Vignali, KM, Vignali, DAA, Mariuzza, RA, Orban, J
JournalJ Biol Chem
Date Published2015 Jun 24
ISSN1083-351X
Abstract<p>The T cell receptor (TCR)-CD3 complex is composed of a genetically diverse αβ TCR heterodimer associated noncovalently with the invariant CD3 dimers CD3ϵγ, CDϵδ and CD3ζζ. The TCR mediates peptide-MHC recognition, while the CD3 molecules transduce activation signals to the T cell. Whereas much is known about downstream T cell signaling pathways, the mechanism whereby TCR engagement by peptide-MHC initiates signaling is poorly understood. A key to solving this problem is defining the spatial organization of the TCR-CD3 complex and the interactions between its subunits. We have applied solution NMR methods to identify the docking site for CD3 on the β chain of a human autoimmune TCR. We demonstrate a low affinity but highly specific interaction between the extracellular domains of CD3 and the TCR constant β (Cβ) domain that requires both CD3ϵγ and CD3ϵδ subunits. The mainly hydrophilic docking site, comprising 9-11 solvent accessible Cβ residues, is relatively small (~400 A2), consistent with the weak interaction between TCR and CD3 extracellular domains, and devoid of glycosylation sites. The docking site is centered on the αA and αB helices of Cβ, which are located at the base of the TCR. This positions CD3ϵγ and CD3ϵδ between the TCR and the T cell membrane, permitting us to distinguish among several possible models of TCR-CD3 association. We further correlate structural results from NMR with mutational data on TCR-CD3 interactions from cell-based assays.</p>
DOI10.1074/jbc.M115.663799
Alternate JournalJ. Biol. Chem.
PubMed ID26109064
Grant ListR21 AI101911 / AI / NIAID NIH HHS / United States