Elucidation of trafficking of the Menkes (MNK;ATP7A) copper-transporting ATPase in epthelial cells

铜是所有生物体必需的微量元素。许多过程都需要铜，包括能量代谢，制造和维持具有足够弹性的强壮骨骼和动脉，大脑中化学递质的合成以及清除有毒自由基的反应。铜也被用于蛋白质，这些蛋白质与重要的神经系统疾病有关，包括阿尔茨海默病和疯牛病。Menkes病是一种遗传性的，通常是致命的人类铜缺乏症，这种疾病与上述器官和组织有关的多种有害症状是铜的重要性的明显指标。我们对Menkes病进行了广泛的研究，特别是Menkes蛋白，它在正常个体中在维持细胞中的铜平衡方面起着重要作用，即足够的铜满足细胞的营养需求，但不会太多，这会导致毒性。正常的Menkes蛋白催化铜穿过细胞膜运输到铜依赖酶所需的区域，并且对于铜从肠道吸收到体内至关重要。正常的Menkes蛋白质起着分子泵的作用。我们已经发现，这种蛋白质可以感知细胞中的铜浓度，当这些浓度达到潜在的毒性水平时，它可以通过小泡移动（交通）到细胞周围的质膜。在那里，它将多余的铜从细胞中泵出并返回其原始位置。我们的研究旨在了解允许这种非凡的蛋白质在活细胞中实现铜平衡的分子机制。这些发现将对理解和治疗涉及铜缺乏或铜毒性的获得性和遗传性疾病，包括骨质疏松症，心血管疾病和阿尔茨海默病具有重要意义。

Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper deficiency disorder in humans, and the diverse and detrimental symptoms of this disease related to organs and tissues described above is a stark indicator of the essentiality of copper. We have carried out extensive research on Menkes disease and in particular the Menkes protein which in normal individuals plays a major role in maintaining the copper balance in cells, i.e. enough copper to satisfy nutritional needs of cells but not too much which causes toxicity. The normal Menkes protein catalyses the transport of copper across membranes of cells to the areas where it is needed by copper-dependent enzymes and is essential for copper absorption into the body from the gut. The normal Menkes protein functions as a molecular pump. We have discovered that this protein can sense copper concentrations in the cell and when these reach potentially toxic levels it can move (traffic) via small vesicles to the plasma membrane which surrounds cells. There it pumps the excess copper out of the cell and returns to its original location. Our studies are directed to understanding the molecular mechanisms which permit this remarkable protein to achieve a copper balance in living cells. The findings will be of major significance in understanding and treating acquired and inherited diseases involving copper deficiency or copper toxicity including osteoporosis, cardiovascular disease, and Alzheimer's disease.