Sequence Determinants of the Aggregation of Proteins Within Condensates Generated by Liquid-liquid Phase Separation |
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Institution: | 1. Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, UK;2. Department of Biomedical Sciences, University of Padova, Italy;3. Department of Biochemistry and Molecular Biology, University of Debrecen, Hungary |
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Abstract: | 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. |
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Keywords: | liquid-liquid phase separation aggregation biomolecular condensates protein interactions ALS mutations |
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