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Phosphorylation of T cell receptor ζ is regulated by a lipid dependent folding transition

Nature Structural Biology volume 7, pages 1023–1026 (2000)Cite this article

Abstract

The cytoplasmic domain of the T cell receptor ζ subunit (ζcyt) is sufficient to couple receptor ligation to intracellular signaling cascades, but little is known about its structure or mechanism of signaling. In aqueous solution, ζcyt is unstructured. Here we report that in the presence of lipid vesicles ζcyt assumes a folded structure. The folding transition is reversible and dependent on the presence of acidic phospholipids. In the lipid-bound conformation, ζcyt is refractory to phosphorylation by src family tyrosine kinases, which are believed to play a key role in signal initiation in vivo. In the lipid-free, unstructured form, ζcyt is readily phosphorylated, and phospho-ζcyt exhibits neither membrane association nor structure induction. The conformational change may provide a mechanism for coupling receptor clustering to cytoplasmic signaling events.

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Figure 1: Acidic phospholipids induce folding of the cytoplasmic domain of TCRζ.
Figure 2: Lipid binding activity of the cytoplasmic domain of TCR ζ.
Figure 3: Lipid association blocks phosphorylation of ζcyt by src(86–536).
Figure 4: Multiply phosphorylated ζcyt does not exhibit lipid dependent folding and binding activities.
Figure 5: Model for T cell signal transduction through the ζ subunit. In the pre-activation state, ζcyt is bound to the inner leaflet of the membrane.

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Acknowledgements

We thank W. Weissenhorn, S. Harrison and M. Eck for materials. This work was supported by a Career Development Award from the National Science Foundation (L.J.S.), a grant from the National Center for Research Resources for purchase of the BIAcore instrument, and a training grant from the NIH (D.A.).

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Authors and Affiliations

  1. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Dikran Aivazian

  2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139 , Massachusetts, USA

    Lawrence J. Stern

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  1. Dikran Aivazian
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Correspondence to Lawrence J. Stern.

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Aivazian, D., Stern, L. Phosphorylation of T cell receptor ζ is regulated by a lipid dependent folding transition. Nat Struct Mol Biol 7, 1023–1026 (2000). https://doi.org/10.1038/80930

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