Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation.
Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation.
复制标题
锌抑制 Hedgehog 自动加工：将锌缺乏与 Hedgehog 激活联系起来。
DOI：
10.1074/jbc.m114.623264
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Wang,Chunyu
中科院分区：
文献类型：
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作者：
Xie,Jian;Owen,Timothy;Xia,Ke;Singh,AjayVikram;Tou,Emiley;Li,Lingyun;Arduini,Brigitte;Li,Hongmin;Wan,LeoQ;Callahan,Brian;Wang,Chunyu
锌是一种具有广泛生物学功能的必需金属，而Hedgehog（Hh）信号在发育和疾病中起着至关重要的作用。在这里，我们描述了锌和Hh信号之间的相互作用机制。Hh配体（Hh ligand）是Hh信号的上游激活因子，它来源于Hh前体蛋白的自切割和胆固醇修饰过程。体外实验显示锌抑制Hh的自加工，IC_（50）为2 μM。溶液NMR显示锌与Hh自加工结构域的活性位点残基相互作用，而ITC表明结合主要由1：1化学计量的焓驱动。我们通过细胞培养研究进一步证明了锌对Hh自动加工的抑制延伸到细胞环境。在正常生理学中，锌可能作为Hh自加工的负调节剂，并抑制Hh配体和Hh信号的产生。在许多疾病中，锌缺乏和Hh配体水平升高共存，包括前列腺癌、肺癌、卵巢癌和自闭症。我们的数据表明，锌缺乏和Hh配体的过度产生之间存在一种新的因果关系：锌缺乏可能会增强Hh的自动加工和Hh配体的产生，从而激活疾病中的Hh信号。
Zinc is an essential metal with wide-ranging biological functions while Hedgehog (Hh) signaling plays crucial roles in both development and disease. Here we describe a mechanistic interaction between zinc and Hh signaling. Hh ligand, the upstream activator of Hh signaling, originates from Hh autoprocessing, in which Hh precursor protein undergoes self-cleavage and cholesterol modification. In vitro assay showed zinc inhibits Hh autoprocessing with IC50 of 2 μM. Solution NMR revealed that zinc interacts with active site residues of Hh autoprocessing domain while ITC indicated that the binding is driven mostly by enthalpy with 1: 1 stoichiometry. We further demonstrated zinc inhibition of Hh autoprocessing extends to a cellular environment through cell culture studies. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer and autism. Our data suggest a novel, causal relationship between zinc deficiency and the overproduction of Hh ligand: zinc deficiency likely enhances Hh autoprocessing and the production of Hh ligand, thereby activating Hh signaling in diseases.