Phase separation of signaling molecules promotes T cell receptor signal transduction

By Xiaolei Su, Jonathon A. Ditlev, E. Hui, Wenmin Xing, Sudeep Banjade, Julia Okrut, D. King, J. Taunton, M. Rosen, R. Vale. Science, 2016

1,149 citations recorded by the source corpus.

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.

Subfields: Immunology, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/32309c8a4469f503d78e29d6fc755543e51657f6

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Citations in the corpus

Liquid-Liquid Phase Separation in Disease. (2019, background): “When the TCR is activated, downstream effector proteins spontaneously phase separate into dynamic membrane-associated clusters (142).”
Liquid phase condensation in cell physiology and disease (2017, background): “Recent work shows that these SH3/PRM–driven phase transitions can also promote signaling outputs both in an in vitro reconstituted system and in living cells (136).”
Stress-triggered phase separation is an adaptive, evolutionarily tuned response (2017, background): “, 2016) or compartmentalized signaling molecules (Su et al., 2016).”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “In light of this, different membrane receptors achieve exactly this through protein phase separation [6,8].”
Sequence determinants of protein phase behavior from a coarse-grained model (2017, background): “First, 18 the formation and dissolution processes can be tuned by the cellular environment such 19 as changes in temperature, pH and salt concentration [25], by post-translational 20 modification such as phosphorylation [19,26], and by mixing with other biomolecules 21 such as proteins [27], RNA [28”