Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Adv Protein Chem Struct Biol. 2018;110:123-165. doi: 10.1016/bs.apcsb.2017.09.001. Epub 2017 Oct 18.
The ubiquitin-proteasome pathway (UPP) is a major venue for controlled intracellular protein degradation in Eukaryota. The machinery of several hundred proteins is involved in recognizing, tagging, transporting, and cleaving proteins, all in a highly regulated manner. Short-lived transcription factors, misfolded translation products, stress-damaged polypeptides, or worn-out long-lived proteins, all can be found among the substrates of UPP. Carefully choreographed protein-protein interactions (PPI) are involved in each step of the pathway. For many of the steps small-molecule inhibitors have been identified and often they directly or indirectly target PPI. The inhibitors may destabilize intracellular proteostasis and trigger apoptosis. So far this is the most explored option used as an anticancer strategy. Alternatively, substrate-specific polyubiquitination may be regulated for a precise intervention aimed at a particular metabolic pathway. This very attractive opportunity is moving close to clinical application. The best known drug target in UPP is the proteasome: the end point of the journey of a protein destined for degradation. The proteasome alone is a perfect object to study the mechanisms and roles of PPI on many levels. This giant protease is built from multisubunit modules and additionally utilizes a service from transient protein ligands, for example, delivering substrates. An elaborate set of PPI within the highest-order proteasome assembly is involved in substrate recognition and processing. Below we will outline PPI involved in the UPP and discuss the growing prospects for their utilization in pharmacological interventions.
泛素-蛋白酶体途径（UPP）是真核生物中控制细胞内蛋白质降解的主要场所。几百种蛋白质的机器参与识别、标记、运输和切割蛋白质，所有这些都是以高度调控的方式进行的。短寿命转录因子、错误折叠的翻译产物、应激损伤的多肽或磨损的长寿命蛋白质，都可以在 UPP 的底物中找到。精心编排的蛋白质-蛋白质相互作用（PPI）涉及途径的每一步。对于许多步骤，已经确定了小分子抑制剂，并且它们经常直接或间接地靶向 PPI。抑制剂可能破坏细胞内蛋白质稳态并引发细胞凋亡。到目前为止，这是作为抗癌策略最广泛探索的选择。或者，可以对特定代谢途径进行有针对性的干预，以调节底物特异性多泛素化。这个非常有吸引力的机会正在接近临床应用。UPP 中最著名的药物靶点是蛋白酶体：蛋白质降解命运的终点。蛋白酶体本身就是研究 PPI 在许多层面上的机制和作用的完美对象。这个巨大的蛋白酶是由多亚基模块构建的，此外还利用了瞬时蛋白质配体的服务，例如，输送底物。在最高阶的蛋白酶体组装中，有一套精心设计的 PPI 参与了底物的识别和加工。下面我们将概述 UPP 中涉及的 PPI，并讨论它们在药理学干预中的应用前景。
