Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound
Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound
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DOI：
10.1016/j.chembiol.2019.07.001
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发表时间：
2019-09-19
影响因子：
8.6
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
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作者：
Ehrnhoefer, Dagmar E.;Skotte, Niels H.;Hayden, Michael R.
在没有其他凋亡标志的情况下，胱天蛋白酶-6（C6）的异常激活已在来自亨廷顿病（HD）患者和动物模型的细胞和组织中得到证实。C6活性与HD患者的疾病进展相关，突变型亨廷顿蛋白（mHTT）的裂解被认为是疾病发病机制的重要因素。在这里，我们表明，由C6裂解产生的mEITT（1-586）片段与酶的酶原形式相互作用，稳定含有活性位点的构象，并易于完全激活。这种向增强活性的转变可以通过阻断C6和mEITT之间相互作用的小分子抑制剂来阻止（1-586）。分子对接研究表明，抑制剂结合的变构位点的C6酶原。因此，mHTT（1-586）与C6的相互作用可能会促进C6酶原激活和mHTT裂解的自我增强、前馈循环，从而驱动HD发病机制。
Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mEITT(1-586) fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mEITT(1-586). Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT(1-586) with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.