Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20.
Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20.
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DOI：
10.1016/j.molcel.2016.05.031
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发表时间：
2016-07-21
期刊：
影响因子：
16
通讯作者：
Zheng N
中科院分区：
文献类型：
--
作者：
Li H;Lim KS;Kim H;Hinds TR;Jo U;Mao H;Weller CE;Sun J;Chatterjee C;D'Andrea AD;Zheng N
泛素特异性蛋白酶（USP）是最大的去泛素化酶家族，其催化活性通常通过未知的机制由其结合伴侣调节。在这里，我们报告了一系列的晶体学和生物化学分析的进化保守的去泛素化酶，USP 12，这是由两个β-螺旋桨蛋白，UAF 1和WDR 20激活。我们的结构揭示了UAF 1和WDR 20在远离其催化中心的两个不同位点与USP 12相互作用。在不增加USP 12的底物亲和力的情况下，两种β-螺旋桨蛋白通过不同的变构机制增强酶。UAF 1停靠在USP 12 Fingers结构域的远端，并诱导一系列结构变化，这些变化到达邻近催化裂缝的关键泛素接触环。相比之下，WDR 20锚定在这个环的底部，并远程调节酶的催化中心。我们的研究结果提供了一个机制的例子，变构激活的USP的监管伙伴。
Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far away from its catalytic center. Without increasing substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach to a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.