期刊
CELL CHEMICAL BIOLOGY
卷 26, 期 9, 页码 1295-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2019.07.001
关键词
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资金
- Canadian Institutes of Health Research [CIHR 20R90174]
- Baden-Wurttemberg-Stiftung through the program Internationale Spitzenforschung
- Teva Pharmaceuticals
- NIH [AI135489]
- CIHR
- Austrian Science funds (FWF)
- James Family
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.
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