The autolysis of human HtrA1 is governed by the redox state of its N-terminal domain.
The autolysis of human HtrA1 is governed by the redox state of its N-terminal domain.
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人类HTRA1的自溶液受其N末端结构域的氧化还原状态的控制。
DOI：
10.1021/bi401633w
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发表时间：
2014-06-17
期刊：
影响因子：
2.9
通讯作者：
Enghild, Jan J.
中科院分区：
文献类型：
--
作者：
Risor, Michael W.;Poulsen, Ebbe Toftgaard;Thomsen, Line R.;Dyrlund, Thomas F.;Nielsen, Tania A.;Nielsen, Niels Chr;Sanggaard, Kristian W.;Enghild, Jan J.
人类HtrA1（高温需要蛋白A1）属于一个保守的丝氨酸蛋白酶家族，参与蛋白质质量控制和细胞命运。这种三聚体普遍表达的蛋白酶具有凝乳胰蛋白酶样特异性，主要针对选择的或错误折叠的底物蛋白中的疏水延伸。此外，该酶能够通过去除n端胰岛素样生长因子结合蛋白(IGFBP)/ kazal样串联基序而发挥自溶活性，而不影响蛋白酶活性。在这项研究中，我们已经解决了控制自溶活性的机制，并发现它取决于n端IGFBP/ kazal结构域中二硫键的完整性。自溶裂解的特异性揭示了HtrA1 P1位置的半胱氨酸的强烈偏好，解释了在二硫还原之前缺乏自溶的原因。值得注意的是，二硫化物被硫氧还蛋白还原，这表明体内HtrA1的自溶与内源性氧化还原平衡有关，并且n端结构域充当氧化还原感应开关。
Human HtrA1 (high-temperature requirement protein A1) belongs to a conserved family of serine proteases involved in protein quality control and cell fate. The homotrimeric ubiquitously expressed protease has chymotrypsin-like specificity and primarily targets hydrophobic stretches in selected or misfolded substrate proteins. In addition, the enzyme is capable of exerting autolytic activity by removing the N-terminal insulin-like growth factor binding protein (IGFBP)/Kazal-like tandem motif without affecting the protease activity. In this study, we have addressed the mechanism governing the autolytic activity and find that it depends on the integrity of the disulfide bonds in the N-terminal IGFBP/Kazal-like domain. The specificity of the autolytic cleavage reveals a strong preference for cysteine in the P1 position of HtrA1, explaining the lack of autolysis prior to disulfide reduction. Significantly, the disulfides were reduced by thioredoxin, suggesting that autolysis of HtrA1 in vivo is linked to the endogenous redox balance and that the N-terminal domain acts as a redox-sensing switch.
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