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首页> 外文期刊>Journal of Molecular Biology >Ubiquitin is a novel substrate for human insulin-degrading enzyme.
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Ubiquitin is a novel substrate for human insulin-degrading enzyme.

机译：泛素是人胰岛素降解酶的新型底物。

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Insulin-degrading enzyme (IDE) can degrade insulin and amyloid-beta, peptides involved in diabetes and Alzheimer's disease, respectively. IDE selects its substrates based on size, charge, and flexibility. From these criteria, we predict that IDE can cleave and inactivate ubiquitin (Ub). Here, we show that IDE cleaves Ub in a biphasic manner, first, by rapidly removing the two C-terminal glycines (k(cat)=2 s(-1)) followed by a slow cleavage between residues 72 and 73 (k(cat)=0.07 s(-1)), thereby producing the inactive 1-74 fragment of Ub (Ub1-74) and 1-72 fragment of Ub (Ub1-72). IDE is a ubiquitously expressed cytosolic protein, where monomeric Ub is also present. Thus, Ub degradation by IDE should be regulated. IDE is known to bind the cytoplasmic intermediate filament protein nestin with high affinity. We found that nestin potently inhibits the cleavage of Ub by IDE. In addition, Ub1-72 has a markedly increased affinity for IDE ( approximately 90-fold). Thus, the association of IDE with cellular regulators and product inhibition by Ub1-72 can prevent inadvertent proteolysis of cellular Ub by IDE. Ub is a highly stable protein. However, IDE instead prefers to degrade peptides with high intrinsic flexibility. Indeed, we demonstrate that IDE is exquisitely sensitive to Ub stability. Mutations that only mildly destabilize Ub (DeltaDeltaG<0.6 kcal/mol) render IDE hypersensitive to Ub with rate enhancements greater than 12-fold. The Ub-bound IDE structure and IDE mutants reveal that the interaction of the exosite with the N-terminus of Ub guides the unfolding of Ub, allowing its sequential cleavages. Together, our studies link the control of Ub clearance with IDE.
机译：胰岛素降解酶（IDE）可以降解分别与糖尿病和阿尔茨海默氏病有关的胰岛素和淀粉样β肽。 IDE会根据尺寸，电荷和灵活性来选择其基板。根据这些标准，我们预测IDE可以裂解和灭活泛素（Ub）。在这里，我们显示IDE以双相方式切割Ub，首先通过快速去除两个C末端甘氨酸（k（cat）= 2 s（-1）），然后在残基72和73（k（ cat）= 0.07 s（-1）），从而产生Ub的非活性1-74片段（Ub1-74）和Ub的1-72片段（Ub1-72）。 IDE是一种普遍表达的胞质蛋白，也存在单体Ub。因此，应该控制IDE对Ub的降解。已知IDE以高亲和力结合细胞质中间丝蛋白巢蛋白。我们发现Nestin可以有效抑制IDE裂解Ub。此外，Ub1-72对IDE的亲和力显着提高（大约90倍）。因此，IDE与细胞调节剂的结合以及Ub1-72对产物的抑制作用可防止IDE对细胞Ub的无意蛋白水解。 Ub是高度稳定的蛋白质。但是，IDE更喜欢降解具有高固有柔韧性的肽。实际上，我们证明了IDE对Ub稳定性非常敏感。仅轻微破坏Ub稳定性的突变（DeltaDeltaG <0.6 kcal / mol）使IDE对Ub敏感，速率增加幅度大于12倍。结合Ub的IDE结构和IDE突变体表明异位点与Ub的N末端的相互作用指导Ub的展开，从而允许其顺序裂解。总之，我们的研究将对Ub清除的控制与IDE相联系。

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