Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.
Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.
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通过化学诱导副催化颠覆刺猬蛋白自动加工。
DOI：
10.1021/acs.biochem.0c00013
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发表时间：
2020
期刊：
影响因子：
2.9
通讯作者：
Callahan,BrianP
中科院分区：
文献类型：
--
作者：
Smith,CarlJ;Wagner,AndrewG;Stagnitta,RobertT;Xu,Zihan;Pezzullo,JohnL;Giner,José-Luis;Xie,Jian;Covey,DouglasF;Wang,Chunyu;Callahan,BrianP
刺猬蛋白是一种重要的细胞信号因子家族，以前体形式表达，这需要特殊的自动处理，称为胆固醇分解，以获得充分的生物活性。胆碱酯分解是通过前体的C末端酶切域HHC的作用而发生的。在这项工作中，我们描述了HHC激活剂化合物(HAC)，这是一类新型的非共价调节剂，可以诱导自动加工不忠，减少天然胆固醇分解，有利于前体自身蛋白分解，否则是一种轻微的和明显的非生理性副反应。HAc诱导的自身蛋白分解产生无胆固醇的Hedgehog蛋白，因此信号缺陷。最有效的HAc具有9μM的AC50值，将HHC的自蛋白分解活性提高225倍，并在存在和不存在天然底物胆固醇的情况下发挥作用。HAC加入了一类罕见的“拮抗剂”，它们通过颠覆机制的保真度来抑制本土酶的活性。
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 occursin cisthrough 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 AC50of 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.