The Molecular Basis for Ubiquitin and Ubiquitin-like Specificities in Bacterial Effector Proteases.
The Molecular Basis for Ubiquitin and Ubiquitin-like Specificities in Bacterial Effector Proteases.
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DOI：
10.1016/j.molcel.2016.06.015
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发表时间：
2016-07-21
期刊：
影响因子：
16
通讯作者：
Komander D
中科院分区：
文献类型：
--
作者：
Pruneda JN;Durkin CH;Geurink PP;Ovaa H;Santhanam B;Holden DW;Komander D
病原菌依靠分泌的效应蛋白来操纵宿主信号通路，通常是以创造性的方式。CE家族蛋白酶是真核生物中泛素样修饰的特异性水解酶（SUMO和NEDD 8），据报道作为具有去SUMO酶、去泛素酶或甚至乙酰转移酶活性的细菌效应蛋白。在这里，我们表征细菌CE蛋白酶活性，揭示K63-连接特异性去泛素化酶在人类病原体，如沙门氏菌，埃希氏菌，志贺氏菌，以及在衣原体，立克次体，黄单胞菌的泛素/泛素样交叉反应酶。五种晶体结构，包括泛素/泛素样复合物，解释了底物特异性，并重新定义了CE家族之间的关系。重要的是，这项工作确定了新的家族成员，并提供了以前报道的效应器中的关键发现，如黄单胞菌XopD中意想不到的去泛素化酶活性，由非结构化的泛素结合区贡献。此外，辅助结构域调节特性，如亚细胞定位，如鼠伤寒沙门氏菌SseL中的泛素结合结构域所示。我们的工作突出和解释了不同CE家族蛋白之间观察到的功能适应。细菌CE蛋白酶表现出独特的泛素/泛素样特异性通过三个共同区域的变异性获得底物特异性结构和功能数据重新定义跨界CE家族关系CE效应子与调节功能的辅助结构域相匹配研究了一个蛋白酶家族，该家族对泛素和泛素样修饰表现出明显不同的特异性。利用结构和功能数据，作者得出了实现底物特异性的机制，并重新定义了酶家族在生命王国中的关系。
Pathogenic bacteria rely on secreted effector proteins to manipulate host signaling pathways, often in creative ways. CE clan proteases, specific hydrolases for ubiquitin-like modifications (SUMO and NEDD8) in eukaryotes, reportedly serve as bacterial effector proteins with deSUMOylase, deubiquitinase, or, even, acetyltransferase activities. Here, we characterize bacterial CE protease activities, revealing K63-linkage-specific deubiquitinases in human pathogens, such as Salmonella, Escherichia, and Shigella, as well as ubiquitin/ubiquitin-like cross-reactive enzymes in Chlamydia, Rickettsia, and Xanthomonas. Five crystal structures, including ubiquitin/ubiquitin-like complexes, explain substrate specificities and redefine relationships across the CE clan. Importantly, this work identifies novel family members and provides key discoveries among previously reported effectors, such as the unexpected deubiquitinase activity in Xanthomonas XopD, contributed by an unstructured ubiquitin binding region. Furthermore, accessory domains regulate properties such as subcellular localization, as exemplified by a ubiquitin-binding domain in Salmonella Typhimurium SseL. Our work both highlights and explains the functional adaptations observed among diverse CE clan proteins. Bacterial CE proteases exhibit distinct ubiquitin/ubiquitin-like specificities Substrate specificity is acquired through variability in three common regions Structural and functional data redefine CE clan relationships across kingdoms CE effectors are fitted with accessory domains that modulate function Focusing on examples from pathogenic bacteria, Pruneda et al. examine a family of proteases that displays remarkably distinct specificities toward ubiquitin and ubiquitin-like modifications. Leveraging structural and functional data, the authors derive mechanisms through which substrate specificity is achieved and redefine relationships within the enzyme family across kingdoms of life.