Caspase全稱為含半胱氨酸的天冬氨酸蛋白水解酶，是一組存在于細(xì)胞質(zhì)中具有類似結(jié)構(gòu)的蛋白酶,。它們的活性位點(diǎn)均包含半胱氨酸殘基，能夠特異性的切割靶蛋白天冬氨酸殘基后的肽鍵,。caspase-6是caspase家族的一種,，它的底物是lamin A和keratin18，它們的降解導(dǎo)會(huì)致核纖層和細(xì)胞骨架的崩解,。
近年來,，由于caspase-6(CASP6)關(guān)聯(lián)于神經(jīng)變性疾病以及軸突修剪事件，并且它在亨丁頓舞蹈癥(HD)和阿爾茨海默病(AD)中其決定性作用,，它已經(jīng)被看作一個(gè)有效的藥物靶點(diǎn),。但是，通過ARK5介導(dǎo)的Ser257磷酸化導(dǎo)致CASP6的活性被抑制的機(jī)制尚不明確,。近日,，北大生命科學(xué)學(xué)院蘇曉東教授及其團(tuán)隊(duì)利用晶體結(jié)構(gòu)分析、分子動(dòng)力學(xué)(MD)模擬以及生化分析闡明了該機(jī)理,。相關(guān)研究發(fā)表在3月20日的美國(guó)《生化周刊》（Journal of Biological Chemistry）上,。
在該項(xiàng)研究中,，研究人員分析了ΔproCASP6S257E以及p20/p10S257E的晶體結(jié)構(gòu),，發(fā)現(xiàn)ΔproCASP6S257E以及p20/p10S257E可以各自的模擬磷酸化的CASP6酶原并激活CASP6。結(jié)構(gòu)研究連同大量的生化分析以及分子動(dòng)力學(xué)模擬研究表明：Ser257的磷酸化會(huì)通過維持蛋白在一定的抑制狀態(tài)來抑制CASP6酶原的自我激活,。結(jié)構(gòu)學(xué)以及生化結(jié)果表明,，Ser257的磷酸化還會(huì)通過位阻效應(yīng)來抑制CASP6的活性。
此次研究揭示了磷酸化抑制CASP6的機(jī)制,，也為CASP6有關(guān)的藥物設(shè)計(jì)提供了新的策略,。（生物谷Deepblue編譯）
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..
