Sequence Determinants of the Aggregation of Proteins Within Condensates Generated by Liquid-liquid Phase Separation

The transition between the native and amyloid states of proteins can proceed via a deposition pathway via oligomeric intermediates or via a condensation pathway involving liquid droplet intermediates generated through liquid-liquid phase separation. While several computational methods are available to perform sequence-based predictions of the propensity of proteins to aggregate via the deposition pathway, much less is known about the physico-chemical principles that underlie aggregation within condensates. Here we investigate the sequence determinants of aggregation via the condensation pathway, and identify three relevant features: droplet-promoting propensity, aggregation-promoting propensity and multimodal interactions quantified by the binding mode entropy. By using this approach, we show that it is possible to predict aggregation-promoting mutations in droplet-forming proteins associated with amyotrophic lateral sclerosis (ALS). This analysis provides insights into the amino acid code for the conversion of proteins between liquid-like and solid-like condensates. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study investigates the sequence determinants of protein aggregation via the condensation pathway and identifies three relevant features: droplet-promoting propensity, aggregation-promoting propensity, and multimodal interactions quantified by the binding mode entropy. By using this approach, aggregation-promoting mutations in droplet-forming proteins associated with amyotrophic lateral sclerosis (ALS) can be predicted.