The 14-3-3 family proteins are vital scaffold proteins that ubiquitously expressed in various tissues. They interact with numerous protein targets and mediate many cellular signaling pathways. The 14-3-3 binding motifs are often embedded in intrinsically disordered regions which are closely associated with liquid–liquid phase separation (LLPS). 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. While extensive investigations have been performed on 14-3-3 proteins, its involvement in LLPS is overlooked. To date, 14-3-3 proteins have not been reported to undergo LLPS alone or regulate LLPS of their binding partners. 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. We further analyzed the phase separation behavior of representative 14-3-3 binders and discussed how 14-3-3 proteins may be involved. 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. 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.

14-3-3 家族蛋白是在各种组织中普遍表达的重要支架蛋白。它们与许多蛋白质靶标相互作用并介导许多细胞信号通路。14-3-3 结合基序通常嵌入与液-液相分离 (LLPS) 密切相关的固有无序区域。在过去的十年中，已经观察到多种蛋白质和生物过程中的 LLPS，表明 LLPS 在无膜细胞器和细胞凝聚物的形成中起基础性作用。虽然已经对 14-3-3 蛋白进行了广泛的研究，但忽略了它在 LLPS 中的作用。迄今为止，尚未报道 14-3-3 蛋白单独经历 LLPS 或调节其结合伙伴的 LLPS。为了揭示 14-3-3 蛋白在 LLPS 中的潜在参与，在这篇综述中，我们总结了 14-3-3 结合伙伴的 LLPS 倾向，发现其中大约一半可能会自发发生 LLPS。我们进一步分析了代表性 14-3-3 粘合剂的相分离行为，并讨论了 14-3-3 蛋白如何参与。通过调节相互作用的构象和化合价并招募其他分子，我们推测 14-3-3 蛋白可以在 LLPS 的背景下有效地调节其靶标的功能。考虑到 14-3-3 蛋白的关键作用，迫切需要研究 14-3-3 蛋白在其靶标的相分离过程中的参与及其潜在机制。我们进一步分析了代表性 14-3-3 粘合剂的相分离行为，并讨论了 14-3-3 蛋白如何参与。通过调节相互作用的构象和化合价并招募其他分子，我们推测 14-3-3 蛋白可以在 LLPS 的背景下有效地调节其靶标的功能。考虑到 14-3-3 蛋白的关键作用，迫切需要研究 14-3-3 蛋白在其靶标的相分离过程中的参与及其潜在机制。我们进一步分析了代表性 14-3-3 粘合剂的相分离行为，并讨论了 14-3-3 蛋白如何参与。通过调节相互作用的构象和化合价并招募其他分子，我们推测 14-3-3 蛋白可以在 LLPS 的背景下有效地调节其靶标的功能。考虑到 14-3-3 蛋白的关键作用，迫切需要研究 14-3-3 蛋白在其靶标的相分离过程中的参与及其潜在机制。