Phase separation of signaling molecules promotes T cell receptor signal transduction
Phase separation organizes signaling In T cell receptors, signaling molecules reorganize into tiny phase separated droplets like oil in water. Su et al. used an in vitro system with artificial membranes and 12 components of the T cell receptor signaling system to closely monitor the role of these molecular clusters (see the Perspective by Dustin and Muller) The clusters formed through phosphorylation dependent association of the linker protein LAT (linker for activation of T cells) with other proteins. These clusters also managed to exclude an inactivating phosphatase and increased the specific activity of enzymes controlling actin polymerization. Science, this issue p. 595; see also p. 516 Phosphorylation regulated molecular aggregation promotes signaling. Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer or submicrometer sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12 component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.
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