PDF(Pubmed)
Abstract：
Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also required for a wide array of additional signaling pathways. A zymogen serine protease, S1P matures through autoproteolysis of two pro-domains, with one cleavage event in the endoplasmic reticulum (ER) and the other in the Golgi. We recently identified the SREBP regulating gene, (SPRING), which enhances S1P maturation and is necessary for SREBP signaling. Here, we report the cryo-EM structures of S1P and S1P-SPRING at sub-2.5 Å resolution. SPRING activates S1P by dislodging its inhibitory pro-domain and stabilizing intra-domain contacts. Functionally, SPRING licenses S1P to cleave its cognate substrate, SREBP2. Our findings reveal an activation mechanism for S1P and provide insights into how spatial control of S1P activity underpins cholesterol homeostasis.
摘要：
位点一蛋白酶（S1P）在高尔基体中进行两个切割事件中的第一个，以激活固醇调节元件结合蛋白（SREBP）并上调脂肪原转录。S1P也是一系列其他信号传导途径所必需的。酶原丝氨酸蛋白酶，S1P通过两个前结构域的自身蛋白水解而成熟，内质网（ER）中的一个切割事件，高尔基体中的另一个切割事件。我们最近发现了SREBP调节基因,(弹簧),它增强S1P成熟，是SREBP信号传导所必需的。这里,我们报告了s1P和S1P-SPRING的低温EM结构，分辨率低于2.5µ。SPRING通过清除其抑制性前结构域和稳定结构域内接触来激活S1P。功能上,SPRING许可S1P切割其同源底物，SREBP2.我们的发现揭示了S1P的激活机制，并提供了S1P活性的空间控制如何支撑胆固醇稳态的见解。
