Ηigh-resolution structure of mammalian PI31-20S proteasome complex reveals mechanism of proteasome inhibition.
Ηigh-resolution structure of mammalian PI31-20S proteasome complex reveals mechanism of proteasome inhibition.
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DOI：
10.1016/j.jbc.2023.104862
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
Demartino, George N.
中科院分区：
文献类型：
--
作者：
Hsu, Hao-Chi;Wang, Jason;Kjellgren, Abbey;Li, Huilin;Demartino, George N.
蛋白酶体催化的蛋白质降解介导和调节许多细胞功能的关键方面，并且是健康和疾病中蛋白质稳态的重要因素。蛋白酶体功能部分地由在催化肽键水解的20S核心颗粒与其结合的多种调节蛋白中的任一种之间形成的蛋白酶体全酶的类型决定。其中一种调节剂PI31以前被鉴定为体外20S蛋白酶体抑制剂，但PI31介导的蛋白酶体抑制的分子机制和可能的生理意义都不清楚。在这里，我们报告了与PI 31复合的哺乳动物20 S蛋白酶体的高分辨率冷冻EM结构。结构表明，PI31的固有无序羧基末端的两个拷贝存在于蛋白酶体的闭门构象的中心腔中，并以阻止底物的蛋白水解但抵抗其自身降解的方式与蛋白酶体催化位点相互作用。两条抑制性多肽链似乎源自从20S圆柱体的相对端进入催化室的PI31单体。我们目前的证据表明，PI 31可以抑制哺乳动物细胞中的蛋白酶体活性，并可能为细胞蛋白质稳态的控制提供调节功能。
Proteasome-catalyzed protein degradation mediates and regulates critical aspects of many cellular functions and is an important element of proteostasis in health and disease. Proteasome function is determined in part by the types of proteasome holoenzymes formed between the 20S core particle that catalyzes peptide bond hydrolysis and any of multiple regulatory proteins to which it binds. One of these regulators, PI31, was previously identified as an in vitro 20S proteasome inhibitor, but neither the molecular mechanism nor the possible physiologic significance of PI31-mediated proteasome inhibition has been clear. Here we report a high-resolution cryo-EM structure of the mammalian 20S proteasome in complex with PI31. The structure shows that two copies of the intrinsically disordered carboxyl terminus of PI31 are present in the central cavity of the closed-gate conformation of the proteasome and interact with proteasome catalytic sites in a manner that blocks proteolysis of substrates but resists their own degradation. The two inhibitory polypeptide chains appear to originate from PI31 monomers that enter the catalytic chamber from opposite ends of the 20S cylinder. We present evidence that PI31 can inhibit proteasome activity in mammalian cells and may serve regulatory functions for the control of cellular proteostasis.
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