Widespread occurrence of the droplet state of proteins in the human proteome

Hardenberg, M.; Horvath, A.; Ambrus, V.; FUXREITER, M.; Vendruscolo, M.

doi:10.1101/2020.10.21.348532

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bioRxiv · 10.1101/2020.10.21.348532

Widespread occurrence of the droplet state of proteins in the human proteome

Hardenberg, M.·Horvath, A.·Ambrus, V.·FUXREITER, M.·Vendruscolo, M.

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Abstract

A wide range of proteins have been reported to condensate into a dense liquid phase, forming a reversible droplet state. Failure in the control of the droplet state can lead to the formation of the more stable amyloid state, which is often disease-related. These observations prompt the question of how many proteins can undergo liquid-liquid phase separation. Here, in order to address this problem, we discuss the biophysical principles underlying the droplet state of proteins by analyzing current evidence for droplet-driver and droplet-client proteins. Based on the concept that the droplet state is stabilized by the large conformational entropy associated with non-specific side-chain interactions, we develop the FuzDrop method to predict droplet-promoting regions and proteins, which can spontaneously phase separate. We use this approach to carry out a proteome-level study to rank proteins according to their propensity to form the droplet state, spontaneously or via partner interactions. Our results lead to the conclusion that the droplet state could be, at least transiently, accessible to most proteins under conditions found in the cellular environment. SignificanceLiquid-liquid phase separation of proteins results in biomolecular condensates, which contribute to the organisation of cellular matter into membraneless organelles. It is still unclear, however, whether these condensates represent a common state of proteins. Here, based on biophysical principles driving phase separation, we report a proteome-wide ranking of proteins according to their propensity to condensate into a droplet state. We analyze two mechanisms for droplet formation - driver proteins can spontaneously phase separate, while client proteins require additional components. We conclude that the droplet state, as the native and amyloid states, is a fundamental state of proteins, with most proteins expected to be capable of undergoing liquid-liquid phase separation via either of these two mechanisms.

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Hardenberg, M., Horvath, A., Ambrus, V., FUXREITER, M., Vendruscolo, M.. 2020-10-21. Widespread occurrence of the droplet state of proteins in the human proteome. https://doi.org/10.1101/2020.10.21.348532

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