2008年,研究人员在细菌中发现了一种特殊的、被称作Pup的小蛋白,它可以附着到其他蛋白质上决定该蛋白命运,进而清理蛋白质,控制或调节细胞内其他重要的生理过程。最近,瑞士联邦理工学院(ETH Zurich)分子生物学与生物物理学研究所Eilika Weber-Ban所带领的研究团队成功发现了肺结核病原体结核杆菌(Mycobacterium tuberculosis)中Pup蛋白的作用机制。同时研究人员在试管内模拟Pup结合到蛋白质上的方式时发现了一种Dop新酶。相关研究发表在2009年6月期Nature Structural & Molecular Biology上,该结果为针对肺结核患者,尤其是病原体已产生抗生素耐药性的患者制定治疗策略提供了新依据。
早在80年代,研究人员在植物、动物和人类等多细胞有机体的细胞中发现了与Pup蛋白类似的泛素蛋白,并被授予了2004年诺贝尔化学奖。但是,直到2008年年底,研究人员才发现这种标记蛋白也存在于细菌中。瑞士联邦理工学院研究人员发现,虽然细菌和人类的标记蛋白在功能上都是确保细胞蛋白质的降解,但它们的结构和作用方式却明显不同。
研究人员指出,由于细菌中的蛋白标记系统与人体不同,因此针对细菌Pup系统的药物对人类副作用很小。(生物谷Bioon.com)
生物谷推荐原始出处:
Nature Structural & Molecular Biology 16, 647 - 651 (2009) 17 May 2009 | doi:10.1038/nsmb.1597
Bacterial ubiquitin-like modifier Pup is deamidated and conjugated to substrates by distinct but homologous enzymes
Frank Striebel1, Frank Imkamp1, Markus Sutter1, Martina Steiner1, Azad Mamedov1 & Eilika Weber-Ban1
In analogy to ubiquitin in eukaryotes, the bacterial protein Pup is attached to lysine residues of substrate proteins, thereby targeting them for proteasomal degradation. It has been proposed that, before its attachment, Pup is modified by deamidation of its C-terminal glutamine to glutamate. Here we have identified Dop (locus tag Rv2112) as the specific deamidase of Pup in Mycobacterium tuberculosis. Deamidation requires ATP as a cofactor but not its hydrolysis. Furthermore, we provide experimental evidence that PafA (locus tag Rv2097) ligates deamidated Pup to the proteasomal substrate proteins FabD and PanB. This formation of an isopeptide bond requires hydrolysis of ATP to ADP, suggesting that deamidated Pup is activated for conjugation via phosphorylation of its C-terminal glutamate. By combining these enzymes, we have reconstituted the complete bacterial ubiquitin-like modification pathway in vitro, consisting of deamidation and ligation steps catalyzed by Pup deamidase (Dop) and Pup ligase (PafA).
ETH Zurich, Institute of Molecular Biology & Biophysics, Zurich, Switzerland.