Caspase全称为含半胱氨酸的天冬氨酸蛋白水解酶，是一组存在于细胞质中具有类似结构的蛋白酶。它们的活性位点均包含半胱氨酸残基，能够特异性的切割靶蛋白天冬氨酸残基后的肽键。caspase-6是caspase家族的一种，它的底物是lamin A和keratin18，它们的降解导会致核纤层和细胞骨架的崩解。
近年来，由于caspase-6(CASP6)关联于神经变性疾病以及轴突修剪事件，并且它在亨丁顿舞蹈症(HD)和阿尔茨海默病(AD)中其决定性作用，它已经被看作一个有效的药物靶点。但是，通过ARK5介导的Ser257磷酸化导致CASP6的活性被抑制的机制尚不明确。近日，北大生命科学学院苏晓东教授及其团队利用晶体结构分析、分子动力学(MD)模拟以及生化分析阐明了该机理。相关研究发表在3月20日的美国《生化周刊》（Journal of Biological Chemistry）上。
在该项研究中，研究人员分析了ΔproCASP6S257E以及p20/p10S257E的晶体结构，发现ΔproCASP6S257E以及p20/p10S257E可以各自的模拟磷酸化的CASP6酶原并激活CASP6。结构研究连同大量的生化分析以及分子动力学模拟研究表明：Ser257的磷酸化会通过维持蛋白在一定的抑制状态来抑制CASP6酶原的自我激活。结构学以及生化结果表明，Ser257的磷酸化还会通过位阻效应来抑制CASP6的活性。
此次研究揭示了磷酸化抑制CASP6的机制，也为CASP6有关的药物设计提供了新的策略。（生物谷Deepblue编译）
doi: 10.1074/jbc.M112.351213
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PMID:
Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal structures, molecular dynamics (MD) simulations and biochemical assays
Qin Cao, Xiao-Jun Wang, Cheng-Wen Liu, Dai-Fei Liu, Lan-Fen Li, Yi-Qin Gao and Xiao-Dong Su.
The apoptotic effector caspase-6 (CASP6) has been clearly identified as a drug-target due to its strong association with neurodegeneration and axonal pruning events, as well as its crucial roles in Huntington disease (HD) and Alzheimer disease (AD). CASP6 activity is suppressed by ARK5 mediated phosphorylation at Ser257 with an unclear mechanism.In this work, we solved crystal structures of ΔproCASP6S257E and p20/p10S257E, which mimicked the phosphorylated CASP6 zymogen and activated CASP6,respectively. The structural investigation combined with extensive biochemical assay and molecular dynamics (MD) simulation studies revealed that phosphorylation on Ser257 inhibited self-activation of CASP6 zymogen by "locking" the enzyme in the TEVD193 bound "inhibited state" .The structural and biochemical results also showed that phosphorylation on Ser257 inhibited the CASP6 activity by steric hindrance.These results disclosed the inhibition mechanism of CASP6 phosphorylation, and laid the foundation for a new strategy of rational CASP6 drug design..
