Structure and Function of the Human Copper Transporter

说明(申请人提供)：铜是生命所必需的，毫不奇怪，铜稳态失衡会导致许多神经退行性疾病的进展，包括阿尔茨海默氏症、克雅各布氏症和帕金森氏病。铜摄取转运蛋白(CTR)家族在包括人类在内的多种真核生物中被发现，是细胞摄取这种重要金属离子所必需的。然而，尽管铜具有重要的生理意义，但目前仍不清楚铜是如何通过CTR蛋白被吸收的，以及如何防止游离铜在细胞质中危险地积累。我假设人类CTR蛋白(HCTR1)已经进化到完成这两个任务，首先在摄取后捕获铜，然后将其直接交给铜伴侣蛋白在细胞内分布。我的具体目标是通过解决hCTR1的3D结构来检验这一假说(目标1)，并确定转运蛋白和伴侣蛋白是否以及如何相互作用来完成铜的吸收(目标2)。预期的结果将是了解铜稳态的里程碑，并可能有助于设计治疗各种神经退行性疾病的新疗法。

DESCRIPTION (provided by applicant): Copper is essential for life and, not surprisingly, imbalances in copper homeostasis contribute to the progression of many neurodegenerative diseases including Alzheimer's, Creutzfeldt-Jakob and Parkinson's disease. The Copper Uptake transporter (CTR) family of proteins, identified in a variety of eukaryotic organisms, including humans, is required for the cellular uptake of this essential metal ion. Despite its physiological importance, however, it is still unclear how copper is taken up through CTR proteins and how a hazardous accumulation of free copper in the cytosol is prevented. I hypothesize that the human CTR protein (hCTR1) has evolved to accomplish both tasks by first trapping copper after uptake and then handing it off directly to copper chaperone proteins for intracellular distribution. My specific aims are designed to test this hypothesis by solving the 3D structure of hCTR1 (Aim 1) and to determine if and how the transporter and chaperone proteins interact to accomplish copper uptake (Aim 2). The expected results will be milestones in the understanding of copper homeostasis and could help in designing new therapeutics for the treatment of a wide assortment of neurodegenerative diseases.