La Fontaine Sharon, Mercer Julian F B
Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, 221 Burwood Highway, Burwood, Vic. 3125, Australia.
Arch Biochem Biophys. 2007 Jul 15;463(2):149-67. doi: 10.1016/j.abb.2007.04.021. Epub 2007 May 7.
Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.
铜对人类健康至关重要，而铜失衡是几种神经退行性疾病病因和病理的关键因素。铜转运P型ATP酶ATP7A和ATP7B是调节和维持哺乳动物铜稳态所需的关键分子。它们的缺失或功能异常分别导致遗传性疾病门克斯病和威尔逊病。这些蛋白质在细胞中具有双重作用，即向必需的铜酶提供铜，并介导细胞内过量铜的排泄。ATP7A和ATP7B的一个独特特征是它们能够感知并响应细胞内铜水平，这一功能通过它们从反式高尔基体网络向适当的细胞膜结构域（分别为基底外侧或顶端）的铜调节转运来体现，以消除细胞内过量的铜。过去十年的研究对铜ATP酶的酶学性质和细胞生物学有了重要的认识。随着最近在阐明它们在人类和动物组织中响应生理刺激的定位和转运方面的进展，我们正迅速朝着在整个动物水平上综合理解它们的生理意义迈进。这些知识反过来不仅有助于阐明由门克斯病和威尔逊病患者个体突变赋予的表型的生化和细胞基础，也有助于阐明与这些疾病相关的临床表型的变异性。重要的是，这些信息还为某些诊断标志物和治疗方案的适用性和合理性提供了理论基础。本综述将介绍我们目前对铜ATP酶在细胞和组织中的定位和转运特性、控制其转运活动的分子信号和翻译后相互作用以及与致病突变相关的临床表型的细胞基础的理解现状。
