Lipid-driven condensation and interfacial ordering of FUS

Abstract

Protein condensation into liquid-like structures is critical for cellular compartmentalization, RNA processing, and stress response. Research on protein condensation has primarily focused on membraneless organelles in the absence of lipids. However, the cellular cytoplasm is full of lipid interfaces, yet comparatively little is known about how lipids affect protein condensation. Here, we show that nonspecific interactions between lipids and the disordered fused in sarcoma low-complexity (FUS LC) domain strongly affect protein condensation. In the presence of anionic lipids, FUS LC formed lipid-protein clusters at concentrations more than 30-fold lower than required for pure FUS LC. Lipid-triggered FUS LC clusters showed less dynamic protein organization than canonical, lipid-free FUS LC condensates. Lastly, we found that phosphatidylserine membranes promoted FUS LC condensates having β sheet structures, while phosphatidylglycerol membranes initiated unstructured condensates. Our results show that lipids strongly influence FUS LC condensation, suggesting that protein-lipid interactions modulate condensate formation in cells.

Interfacing Coacervates with Membranes: From Artificial Organelles and Hybrid Protocells to Intracellular Delivery

“…Recently, Chatterjee et al showed that the presence of SUVs containing anionic DOPS and DOPG lipids could induce the formation of clusters of FUS low complexity (LC) domain and lipids at a 30-fold lower concentration than that needed for FUS LC phase separation in the absence of lipids, caused by FUS LC binding to SUVs and adopting a more ordered conformation (Figure 4e). [58] Such interactions between lipids in the membrane and disordered proteins prone to phase separation likely also occur in cells, where membranes could play a prominent role in the nucleation and localization of cellular condensates. Nevertheless, systematic quantification in vitro using model systems is required to evaluate this role.…”

“…Reproduced with permission. [ 58 ] Copyright 2022, American Association for the Advancement of Science.…”

“…e) Negatively charged lipid membrane DOPG SUVs trigger FUS LC condensation at 10 μm FUS LC. Reproduced with permission [58]. Copyright 2022, American Association for the Advancement of Science.…”

Synthetic Membraneless Droplets for Synaptic‐Like Clustering of Lipid Vesicles

“…[15] The electrostatic or hydrophobic interactions within condensate droplets or between protein sequences and vesicles, as well as the crowded intracellular environments, have been revealed to account for condensate formation and SV-clustering. [6a,16] However, how these interactions, which are also involved in other MLO/ membrane systems, [17] have led to the specific synaptic clustering of vesicles remains unknown.…”

Sensitive Detection of Biomolecular Adsorption by a Low-Density Surfactant Layer Using Sum-Frequency Vibrational Spectroscopy

“…The interaction between the lipid membrane with various molecules (proteins, DNA, inorganic ions) in the solution at different environments has also been studied using sum-frequency vibrational spectroscopy (SFVS). − The change in sum-frequency spectra upon binding of the molecules in the subphase has allowed us to understand the details of the interactions, such as the binding strength or the structural changes at the interface . SFVS was recently applied to study the cation−π interactions by altering the cationic surfactant molecules at the surface and aromatic ring molecules in the subphase .…”