Departments of Biology and Chemistry, Syracuse University, Syracuse, NY, 13244, USA.
Bioinspired Institute, Syracuse University, Syracuse, NY, 13244, USA.
Bioessays. 2020 Nov;42(11):e2000036. doi: 10.1002/bies.202000036. Epub 2020 Sep 3.
Liquid-liquid phase separation (LLPS) has recently emerged as a possible mechanism that enables ubiquitin-binding shuttle proteins to facilitate the degradation of ubiquitinated substrates via distinct protein quality control (PQC) pathways. Shuttle protein LLPS is modulated by multivalent interactions among their various domains as well as heterotypic interactions with polyubiquitin chains. Here, the properties of three different shuttle proteins (hHR23B, p62, and UBQLN2) are closely examined, unifying principles for the molecular determinants of their LLPS are identified, and how LLPS is connected to their functions is discussed. Evidence supporting LLPS of other shuttle proteins is also found. In this review, it is proposed that shuttle protein LLPS leads to spatiotemporal regulation of PQC activities by mediating the recruitment of PQC machinery (including proteasomes or autophagic components) to biomolecular condensates, assembly/disassembly of condensates, selective enrichment of client proteins, and extraction of ubiquitinated proteins from condensates in cells.
液-液相分离（LLPS）最近被认为是一种可能的机制，使泛素结合穿梭蛋白能够通过不同的蛋白质质量控制（PQC）途径促进泛素化底物的降解。穿梭蛋白 LLPS 受到其各种结构域之间的多价相互作用以及与多聚泛素链的异质相互作用的调节。在这里，仔细研究了三种不同的穿梭蛋白（hHR23B、p62 和 UBQLN2）的特性，确定了它们 LLPS 的分子决定因素的统一原则，并讨论了它们的 LLPS 如何与其功能相关联。还发现了支持其他穿梭蛋白 LLPS 的证据。在这篇综述中，提出穿梭蛋白 LLPS 通过介导 PQC 机制（包括蛋白酶体或自噬成分）向生物分子凝聚物的募集、凝聚物的组装/解组装、靶蛋白的选择性富集以及从凝聚物中提取泛素化蛋白，导致 PQC 活性的时空调节。
