[NMR paper] Identification of the Docking Site for CD3 on the T Cell Receptor ? Chain by Solution NMR.

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

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

J Biol Chem. 2015 Aug 7;290(32):19796-805

Authors: He Y, Rangarajan S, Kerzic M, Luo M, Chen Y, Wang Q, Yin Y, Workman CJ, Vignali KM, Vignali DA, Mariuzza RA, Orban J

Abstract
The T cell receptor (TCR)-CD3 complex is composed of a genetically diverse ?? TCR heterodimer associated noncovalently with the invariant CD3 dimers CD3??, CD3??, and CD3??. The TCR mediates peptide-MHC recognition, whereas the CD3 molecules transduce activation signals to the T cell. Although 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 ? 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 ? (C?) domain that requires both CD3?? and CD3?? subunits. The mainly hydrophilic docking site, comprising 9-11 solvent-accessible C? residues, is relatively small (~400 Å(2)), consistent with the weak interaction between TCR and CD3 extracellular domains, and devoid of glycosylation sites. The docking site is centered on the ?A and ?B helices of C?, which are located at the base of the TCR. This positions CD3?? and CD3?? 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.


PMID: 26109064 [PubMed - indexed for MEDLINE]



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