UFM1-Activating Enzyme 5 (Uba5) Requires an Extension to Get the Job Done Right.
UFM1-Activating Enzyme 5 (Uba5) Requires an Extension to Get the Job Done Right.
复制标题
UFM1 激活酶 5 (Uba5) 需要扩展才能正确完成工作。
DOI：
10.1016/j.jmb.2018.11.017
复制
发表时间：
2019
影响因子：
5.6
通讯作者：
Olsen,ShaunK
中科院分区：
文献类型：
--
作者：
Lv,Zongyang;Olsen,ShaunK
泛素（Ub）和Ub样蛋白（Ubls）是翻译后调节剂，通过改变修饰靶蛋白[1]的稳定性、分子间相互作用、活性和定位来调节真核生物的几乎所有方面。Ub/Ubl信号对人类健康的重要性被以下事实所强调：Ub/Ubl信号的失调与许多病理有关，并且该通路可作为癌症和其他疾病治疗干预的目标。所有Ub/Ubls都是通过平行级联酶E1、E2和E3的顺序活性和相互作用结合到靶蛋白上的，这些酶分别用于激活、穿梭和连接Ub/Ubls到靶蛋白[2]。尽管Ub/Ubls及其偶联级联中的酶在结构和机制上是相关的，但它们调节着不同的细胞过程，因此需要机制来确保保真度。这主要是通过E1酶实现的，它作为Ub/Ubl偶联级联的守门人，通过选择性地结合和激活其同源的Ub/Ubl，然后将Ub/Ubl转移到同源的E2s[3-5]。所有E1酶通过atp依赖的两步催化机制激活Ub/Ubls，包括顺序的腺苷化和硫代酯化反应。腺苷化反应包括保守的c端甘氨酸羧酸对ATP α-磷酸的亲核攻击，形成Ub/Ub - amp酰基腺苷酸中间体和焦磷酸离去基。硫代酯化反应涉及E1催化半胱氨酸残基对Ub/Ubl腺苷酸中间体的亲核攻击，在Ub/Ubl的c端甘氨酸和E1催化半胱氨酸之间形成高能硫代酯键，并形成AMP离去基。接下来是E2酶的募集，并将E1催化半胱氨酸的Ub/Ubl转移到E2催化半胱氨酸上，这一过程称为E1-E2-Ubl硫酯转移[3-5]。
Ubiquitin (Ub) and Ub-like proteins (Ubls) are posttranslational modifiers that regulate nearly every aspect of eukaryotic biology by altering the stability, intermolecular interactions, activity, and localization of modified target proteins [1]. The importance of Ub/Ubl signaling to human health is underscored by the fact that its dysregulation is implicated in a number of pathologies and that the pathways serve as targets for therapeutic intervention in cancer and other disorders. All Ub/Ubls are conjugated to target proteins through the sequential activities and interactions of parallel cascades of enzymes called E1, E2, and E3 that together serve to activate, shuttle, and ligate Ub/Ubls to target proteins, respectively [2].Although Ub/Ubls and the enzymes in their conjugation cascades are structurally and mechanistically related, they regulate distinct repertoires of cellular processes, thus requiring mechanisms to ensure fidelity. This is primarily achieved by E1 enzymes, which serve as the gatekeepers of Ub/Ubl conjugation cascades by selectively binding and activating their cognate Ub/Ubls followed by transfer of the Ub/Ubl to cognate E2s [3–5]. All E1 enzymes activate Ub/Ubls through an ATP-dependent two-step catalytic mechanism comprising sequential adenylation and thioesterification reactions. The adenylation reaction comprises nucleophilic attack of a conserved C-terminal glycine carboxylate on the α-phosphate of ATP to form a Ub/Ubl-AMP acyl-adenylate intermediate and a pyrophosphate leaving group. The thioesterification reaction involves nucleophilic attack of the Ub/Ubl adenylate intermediate by the catalytic cysteine residue of E1 to form a high-energy thioester bond between the C-terminal glycine of the Ub/Ubl and the E1 catalytic cysteine along with an AMP leaving group. This is followed by recruitment of E2 enzymes and transfer of the Ub/Ubl from the E1 catalytic cysteine to the E2 catalytic cysteine in a process called E1-E2-Ubl thioester transfer [3–5].