Abstract:
Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), also known as Parkinson\'s disease protein 5, is a highly expressed protein in the brain. It plays an important role in the ubiquitin-proteasome system (UPS), where it acts as a deubiquitinase (DUB) enzyme. Being the smallest member of the UCH family of DUBs, it catalyzes the reaction of ubiquitin precursor processing and the cleavage of ubiquitinated protein remnants, thus maintaining the level of ubiquitin monomers in the brain cells. UCHL1 mutants, containing amino acid substitutions, influence catalytic activity and its aggregability. Some of them protect cells and transgenic mice in toxin-induced Parkinson\'s disease (PD) models. Studies of putative protein partners of UCHL1 revealed about sixty individual proteins located in all major compartments of the cell: nucleus, cytoplasm, endoplasmic reticulum, plasma membrane, mitochondria, and peroxisomes. These include proteins related to the development of PD, such as alpha-synuclein, amyloid-beta precursor protein, ubiquitin-protein ligase parkin, and heat shock proteins. In the context of the catalytic paradigm, the importance of these interactions is not clear. However, there is increasing understanding that UCHL1 exhibits various effects in a catalytically independent manner through protein-protein interactions. Since this protein represents up to 5% of the soluble protein in the brain, PD-related changes in its structure will have profound effects on the proteomes/interactomes in which it is involved. Growing evidence is accumulating that the role of UCHL1 in PD is obviously determined by a balance of canonic catalytic activity and numerous activity-independent protein-protein interactions, which still need better characterization.
摘要:
泛素羧基末端水解酶L1(UCHL1),也被称为帕金森病蛋白5,是一种在大脑中高度表达的蛋白质。它在泛素-蛋白酶体系统(UPS)中起着重要作用,它充当去泛素酶(DUB)酶。作为UCHDUB家族中最小的成员,它催化泛素前体加工的反应和泛素化蛋白残余物的裂解,从而维持脑细胞中泛素单体的水平。UCHL1突变体,含有氨基酸取代,影响催化活性及其聚集性。其中一些在毒素诱导的帕金森病(PD)模型中保护细胞和转基因小鼠。对UCHL1推定的蛋白质伴侣的研究揭示了位于细胞所有主要区室中的约60种单独的蛋白质:细胞核,细胞质,内质网,质膜,线粒体,和过氧化物酶体。这些包括与PD发育相关的蛋白质,比如α-突触核蛋白,淀粉样β前体蛋白,泛素蛋白连接酶parkin,和热休克蛋白。在催化范式的背景下,这些相互作用的重要性尚不清楚。然而,越来越多的人认识到UCHL1通过蛋白质-蛋白质相互作用以催化独立的方式表现出各种作用。由于这种蛋白质占大脑中可溶性蛋白质的5%,其结构的PD相关变化将对其涉及的蛋白质组/相互作用组有深远的影响。越来越多的证据表明,UCHL1在PD中的作用显然是由正则催化活性和众多独立于活性的蛋白质-蛋白质相互作用的平衡决定的。这仍然需要更好的表征。