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Increasing evidences suggest that many types of biomolecular condensates, such as stress granules, P granules, and nuclear speckles, are formed through LLPS. Recently, IDRs have become a theme of many research efforts because they are closely associated with liquid–liquid phase separation (LLPS), which underlies the formation of membraneless organelles and cellular condensates. Consequently, numerous IDRs are involved in cellular regulation and signal transduction. Structural disorder facilitates post-translational modifications (PTMs), association/dissociation kinetics, conformational changes, and so on. While IDRs are unfolded, they perform critical functions. Generally, IDRs lack bulky hydrophobic amino acids and are enriched in charged amino acids. Their amino acid compositions significantly differ from those of folded proteins.

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In contrast to traditional folded protein domains, IDRs do not fold into stable three dimensional structures in the free state. Most of these motifs are embedded in intrinsically disordered regions (IDRs). The binding targets of 14-3-3 proteins usually carry specific motifs containing phosphorylated serine or threonine. Since 14-3-3 proteins are potential therapeutic targets, many 14-3-3 modulators have been discovered/designed to target these specific interactions. Furthermore, 14-3-3 proteins have chaperone activity which may play a role in neurodegenerative disease progression. Dysregulation of 14-3-3 protein expression has been observed in several cancers. Through these protein–protein interactions, 14-3-3 proteins participate in cell cycle regulation, gene expression control, apoptosis, signal transduction, and many other vital biological processes. They interact with numerous protein targets, including kinases, phosphatases, transmembrane receptors, and transcription factors. The name “14-3-3” was given because these proteins elute in the 14th fraction of bovine brain homogenate on the DEAE cellulose column and the 3.3 fraction in the subsequent starch gel electrophoresis. The 14-3-3 proteins are ubiquitously expressed in various tissues and mediate many cellular signaling pathways. Considering the critical roles of 14-3-3 proteins, there is an urgent need for investigating the involvement of 14-3-3 proteins in the phase separation process of their targets and the underling mechanisms. By modulating the conformation and valence of interactions and recruiting other molecules, we speculate that 14-3-3 proteins can efficiently regulate the functions of their targets in the context of LLPS. We further analyzed the phase separation behavior of representative 14-3-3 binders and discussed how 14-3-3 proteins may be involved. To reveal the potential involvement of 14-3-3 proteins in LLPS, in this review, we summarized the LLPS propensity of 14-3-3 binding partners and found that about one half of them may undergo LLPS spontaneously. To date, 14-3-3 proteins have not been reported to undergo LLPS alone or regulate LLPS of their binding partners. While extensive investigations have been performed on 14-3-3 proteins, its involvement in LLPS is overlooked. In the past ten years, LLPS has been observed for a variety of proteins and biological processes, indicating that LLPS plays a fundamental role in the formation of membraneless organelles and cellular condensates. The 14-3-3 binding motifs are often embedded in intrinsically disordered regions which are closely associated with liquid–liquid phase separation (LLPS). They interact with numerous protein targets and mediate many cellular signaling pathways.

The 14-3-3 family proteins are vital scaffold proteins that ubiquitously expressed in various tissues.

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