通过化学诱导副催化来颠覆 Hedgehog 蛋白自加工。
Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.
机构信息
Department of Chemistry , Binghamton University, State University of New York , 4400 Vestal Parkway East , Binghamton , New York 13902 , United States.
Department of Chemistry , State University of New York College of Environmental Science and Forestry , Syracuse , New York 13210 , United States.
出版信息
Biochemistry. 2020 Feb 18;59(6):736-741. doi: 10.1021/acs.biochem.0c00013. Epub 2020 Feb 4.
Hedgehog proteins, a family of vital cell signaling factors, are expressed in precursor form, which requires specialized autoprocessing, called cholesterolysis, for full biological activity. Cholesterolysis occurs through the action of the precursor's C-terminal enzymatic domain, HhC. In this work, we describe HhC activator compounds (HACs), a novel class of noncovalent modulators that induce autoprocessing infidelity, diminishing native cholesterolysis in favor of precursor autoproteolysis, an otherwise minor and apparently nonphysiological side reaction. HAC-induced autoproteolysis generates hedgehog protein that is cholesterol free and hence signaling deficient. The most effective HAC has an AC of 9 μM, accelerates HhC autoproteolytic activity by 225-fold, and functions in the presence and absence of cholesterol, the native substrate. HACs join a rare class of "antagonists" that suppress native enzymatic activity by subverting mechanistic fidelity.
刺猬蛋白是一类重要的细胞信号因子，以前体形式表达，需要专门的自加工，即胆固醇水解，才能发挥完全的生物学活性。胆固醇水解是通过前体 C 端酶结构域 HhC 的作用来实现的。在这项工作中，我们描述了 HhC 激活化合物（HACs），这是一类新型的非共价调节剂，它们诱导自加工的不准确性，降低天然胆固醇水解，有利于前体的自蛋白水解，这是一种次要的、显然非生理的副反应。HAC 诱导的自蛋白水解产生无胆固醇的 hedgehog 蛋白，因此信号缺失。最有效的 HAC 的 AC 值为 9 μM，将 HhC 的自蛋白水解活性加速了 225 倍，并且在有或没有胆固醇（天然底物）的情况下都能发挥作用。HACs 加入了一类罕见的“拮抗剂”，它们通过破坏机制保真度来抑制天然酶活性。
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