Reentrant Liquid Condensate Phase of Proteins is Stabilized by Hydrophobic and Non-Ionic interactions

Georg Krainer,Timothy J Welsh,Jerelle A Joseph,Peter St George-Hyslop,Anthony A Hyman,Rosana Collepardo-Guevara,Simon Alberti,Tuomas P.J Knowles

doi:10.1016/j.bpj.2020.11.426

Georg Krainer, Timothy J Welsh + Show 6 more

Open Access

https://doi.org/10.1016/j.bpj.2020.11.426

Copy DOI

Abstract

Many cellular proteins demix spontaneously from solution to form liquid condensates. These phase-separated structures have wide-ranging roles in health and disease. Elucidating the molecular driving forces underlying liquid-liquid phase separation (LLPS) is therefore a key objective for understanding biological function and malfunction. Here we show that proteins implicated in cellular LLPS, such as FUS, TDP-43, Brd4, Sox2, and Annexin A11, which form condensates at low salt concentrations, can reenter a phase-separated regime at high salt concentrations. Through experiments and simulations, we demonstrate that phase separation in the high-salt regime is mainly driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus provides a new view on the cooperation of hydrophobicity and non-ionic interactions as non-specific driving forces for the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

Highlights

134-Pos A 4BPA Coarse-Grained Molecular Dynamics Study on the Aggregation of Polyglutamine Mark van der Klok, Maurice Dekker, Erik Van der Giessen, Patrick R
The use of denaturing detergents (e.g., SDS) can actively induce protein oligomerization, thereby perturbing the states one wishes to measure. in order to deduce both structural and dynamic information from soluble protein oligomers without perturbing them, we employ a combination of enhanced-sampling molecular dynamics (MD) simulations and solution biophysical tools
These combined techniques allow us to systematically characterize (1) how SDS modulates the aggregation of Islet amyloid polypeptide (IAPP), a 37-residue peptide hormone associated with type II diabetes (T2D), and (2) the extent to which ensemble techniques agree with molecular models of IAPP

Summary

Introduction

134-Pos A 4BPA Coarse-Grained Molecular Dynamics Study on the Aggregation of Polyglutamine Mark van der Klok, Maurice Dekker, Erik Van der Giessen, Patrick R. 132-Pos Reentrant Liquid Condensate Phase of Proteins is Stabilized by Hydrophobic and Non-Ionic interactions Georg Krainer1, Timothy J. Elucidating the molecular driving forces underlying liquid-liquid phase separation (LLPS) is a key objective for understanding biological function and malfunction.

Results

Conclusion