The cytosolic domain of T-cell receptor {zeta} associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer [Signal Transduction]

Interactions between lipid bilayers and the membrane-proximal regions of membrane-associated proteins play important roles in regulat-ing membrane protein structure and function. The T-cell antigen receptor (TCR) is an assembly of eight single-pass membrane-spanning subunits on the surface of T-lymphocytes that initiates cytosolic signaling cascades upon binding antigens presented by MHC-family proteins on antigen-presenting cells. Its ζ subunit contains multiple cytosolic immunoreceptor tyrosine-based activation motifs (ITAMs) involved in signal transduction, and this subunit by itself is sufficient to couple extracellular stimuli to intracellular signaling events. Interactions of the cytosolic domain of ζ (ζcyt) with acidic lipids have been implicated in the initiation and regulation of transmembrane signaling. ζcyt is unstructured in solution. Interaction with acidic phospholipids induces structure, but its disposition when bound to lipid bilayers is controversial. Here, using surface plasmon resonance and neutron reflection, we characterized the inter-action of ζcyt with planar lipid bilayers containing mixtures of acidic and neutral lipids. We observed two binding modes of ζcyt to the bilayers in dynamic equilibrium: one in which ζcyt is peripherally associated with lipid headgroups and one in which it penetrates deeply into the bilayer. Such an equilibrium between the peripherally bound and embedded forms of ζcyt apparently control accessibility of the ITAMs to tyrosine kinases and may regulate the TCR signal transduction pathway. Our results reconcile conflicting findings of the ζ structure reported in previous studies and provide a framework for understanding how lipid interac-tions regulate biological activities for this cell-surface receptor system.

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