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

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.

Energetic and structural features of SARS-CoV-2 N-protein co-assemblies with nucleic acids

“…(Dinesh et al, 2020;Zinzula et al, 2020). Bottom: Propensity of residues to promote LLPS calculated by FuzzDrop, showing in red dropletpromoting regions with p DP >0.6 (Hardenberg et al, 2020). The cartoon depiction highlights oligomeric architecture and interactions, without detail on protein structures.…”

Classifying the Binding Modes of Disordered Proteins

“…The method gives a high performance prediction on the continuum of binding modes of disordered regions, and was validated on ~2000 protein complexes [ 16 , 44 ]. In addition, disordered binding modes were used to predict protein liquid-liquid phase separation, and the results were validated by experiments [ 49 ].…”

Fuzzy protein theory for disordered proteins

“…Application of the fuzzy structure-function model thus opens perspectives to identify context-dependent regulatory motifs in protein networks. This approach can also be used to describe the regulated assembly/disassembly of membraneless organelles [44,63]. Fuzzy structure-function relationships can be integrated into a fuzzy inference system [56], which can model cellular networks with different biological outcomes, similarly to the control system of artificially intelligent devices.…”

“…Such conformational heterogeneity (generated by disorder-to-disorder transitions) is required for driving droplet formation. Thus, protein regions capable of forming disordered binding modes can spontaneously phase separate and serve as scaffolds for droplets [ 44 ]. Other components of condensates, termed as clients, require a partner-induced change in their binding modes.…”