Structure of copper transporting ATPases

描述(由申请人提供)： 所有生物体都有维持金属离子动态平衡的分子系统。P1B型ATPase是一种膜结合的离子转运体，负责重金属的外流，对控制细胞中铜和锌等有益金属的水平以及清除镉和铅等有毒金属至关重要。人类体内的铜ATPase功能障碍会导致遗传性神经疾病，如门克斯综合症和威尔逊病。威尔逊ATPase也与抗癌药物顺铂和卡铂的耐药性有关。这些ATPase跨膜转运金属的机制还不是很清楚。这项提议的目标是结晶和确定来自黄曲霉的CopA的结构，这是一种功能良好的铜运输P1B型ATPase，与Menkes‘s和Wilson’s蛋白都有很强的同源性。COPA的结构表征将有助于阐明铜跨细胞膜转运的机制，并将为了解其人类同源物提供新的视角，这些同源物可能与疾病的治疗和铂类抗肿瘤药物的改进有关。P1B型ATPase的结构将是此类酶中的第一个。

DESCRIPTION (provided by applicant): All organisms have molecular systems that function to maintain metal ion homeostasis. The P1B-type ATPases are membrane-bound ion transporters responsible for the efflux of heavy metals and are essential for controlling the cellular levels of beneficial metals like copper and zinc and removing toxic ones like cadmium and lead. Malfunctioning copper ATPases in humans result in inherited neurological disorders like Menkes' syndrome and Wilson's disease. The Wilson ATPase has also been implicated in promoting resistance to the anticancer drugs cisplatin and carboplatin. The mechanisms of metal transport across membranes by these ATPases are not well understood. The goal of this proposal is to crystallize and determine the structure of CopA from A. fulgidus, a well characterized copper transporting P1B-type ATPase with strong identity to both the Menkes' and Wilson's proteins. Structural characterization of CopA will help to elucidate the mechanism of copper transport across cell membranes and will provide new insight into its human homologues that may be relevant to the treatment of disease and the improvement of platinum based antitumor drugs. The structure of a P1 B-type ATPase will be the first of its kind.