Structure of copper transporting ATPases

描述（由申请人提供）： 所有生物体都具有维持金属离子稳态的分子系统。P1B型ATP酶是负责重金属外排的膜结合离子转运蛋白，对于控制铜和锌等有益金属的细胞水平以及清除镉和铅等有毒金属至关重要。人类铜ATP酶功能障碍导致遗传性神经系统疾病，如门克斯综合征和威尔逊病。Wilson ATP酶也与促进对抗癌药物顺铂和卡铂的耐药性有关。这些ATP酶跨膜转运金属的机制还不清楚。本提案的目标是从A中明确和确定CopA的结构。fulgidus是一种与Menkes蛋白和Wilson蛋白具有很强同一性的铜转运P1B型ATP酶。CopA的结构表征将有助于阐明铜跨细胞膜转运的机制，并将为其人类同系物提供新的见解，这些同系物可能与疾病的治疗和基于铂的抗肿瘤药物的改进有关。P1 B型ATP酶的结构将是同类中的第一个。

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.