Structure and Function of the Human Copper Transporter

描述（由申请人提供）：铜对生命至关重要，铜体内平衡失衡会导致许多神经退行性疾病的进展，包括阿尔茨海默病、克雅氏病和帕金森病。在包括人类在内的多种真核生物中发现的铜摄取转运蛋白（CTR）家族是细胞摄取这种必需金属离子所必需的。然而，尽管铜具有重要的生理意义，但目前尚不清楚铜是如何通过CTR蛋白吸收的，以及如何防止细胞质中游离铜的危险积累。我假设人类CTR蛋白（hCTR1）已经进化到完成这两项任务，首先在摄取铜后捕获铜，然后将其直接传递给铜伴侣蛋白进行细胞内分布。我的具体目标是通过解决hCTR1的3D结构（目标1）来验证这一假设，并确定转运体和伴侣蛋白是否以及如何相互作用以完成铜摄取（目标2）。预期的结果将是理解铜稳态的里程碑，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.