Coupling of protein condensates to ordered lipid domains determines functional membrane organization

Abstract

During T cell activation, the transmembrane adaptor protein LAT (linker for activation of T cells) forms biomolecular condensates with Grb2 and Sos1, facilitating signaling. LAT has also been associated with cholesterol-rich condensed lipid domains; However, the potential coupling between protein condensation and lipid phase separation and its role in organizing T cell signaling were unknown. Here, we report that LAT/Grb2/Sos1 condensates reconstituted on model membranes can induce and template lipid domains, indicating strong coupling between lipid- and protein-based phase separation. Correspondingly, activation of T cells induces cytoplasmic protein condensates that associate with and stabilize raft-like membrane domains. Inversely, lipid domains nucleate and stabilize LAT protein condensates in both reconstituted and living systems. This coupling of lipid and protein assembly is functionally important, as uncoupling of lipid domains from cytoplasmic protein condensates abrogates T cell activation. Thus, thermodynamic coupling between protein condensates and ordered lipid domains regulates the functional organization of living membranes.

ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes

“…We use the term phase coupling to denote this phenomenon. Recent work suggests that similar protein-lipid phase coupling occurs at the plasma membrane and plays an important role in T-cell activation, suggesting a broader role such mechanisms across cellular systems (Chung et al, 2021; Wang et al, 2022).…”

“…Theoretical studies have suggested such a phenomenon might occur (Andes-Koback and Keating, 2011; Nesterov et al, 2021; Rouches et al, 2021). However, direct evidence for such phase coupling has been restricted to interactions between condensates and the plasma membrane (Chung et al, 2021; Lee et al, 2019; Wang et al, 2022).…”

Biomolecular condensates modulate membrane lipid packing and hydration

“…Recently, membranes have been reported to control the size of intracellular condensates and modify their material properties 14 . Furthermore, the crosstalk between membranes and condensates can promote phase separation coupling in the lipid and the protein phases 15,16,17 also shown in cytoplasm mimetic systems 18 . While the field of membrane-condensate interactions is rapidly gaining momentum, important cues are still missing in our understanding of the underlying mechanisms associated with the resulting structural changes and remodeling.…”

Membrane curvature sensing by model biomolecular condensates

“…15 BCs at the cell membrane have been recently shown to function in actin assembly 16 and in a Ras signaling pathway. 17 Evidence of membrane remodeling by BCs has been provided for the N-terminal low-complexity domain of fused in sarcoma (FUS LC), 18 for endocytic coat proteins with intrinsically disordered prion-like domains, 19,20 for transmembrane adaptor Linker of Activation of T-cells (LAT) during T-cell activation, 21 for lipid vesicles within a synapsin-rich liquid phase, 22 and for TIS granules interacting with the endoplasmic reticulum. 23 Such membrane reorganization processes mediated by BCs are anticipated to be a consequence of capillary forces generated at the membrane-condensate interface.…”