FUNCTIONAL DOMAINS OF THE TRANSFERRIN RECEPTOR

该项目的目的是了解转运受体（TfR）和转铁蛋白（Tf）之间的相互作用，以及TfR和血色素沉着症基因产物如何调节铁转运到细胞中。我研究的长期目标是了解这种重要受体的结构和功能。哺乳动物细胞对铁的摄取涉及到Tf与TfR的结合，随后是受体-Tf复合物的内化。铁摄取对细胞分裂至关重要，因此TfR已被确定为增殖特异性标志物。它存在于快速分裂的细胞中。人体和细胞对铁的吸收受到严格控制。哺乳动物体内铁元素过少会导致贫血和发育不良。过多的铁会因氧化损伤而导致铁中毒。遗传性血色素沉着症是一种铁超载的疾病。过量的铁会损害器官，导致肝功能衰竭，成人发病糖尿病，关节炎和心力衰竭。它是欧洲人后裔中最常见的遗传性疾病，大约每400人中就有1人患病。最近，该基因被鉴定并发现与TfR结合。了解铁摄取调控的关键是了解血色素沉着症基因产物之间以及Tf和TfR之间的相互作用。本研究应用程序的具体目标是：绘制这些蛋白质之间的相互作用；确定TfR如何促进核内体中铁的释放；确定血色素沉着病基因产物如何改变Tf和TfR之间的相互作用；最后确定细胞吸收铁的限制因素。

The goals of this project are to understand how the interactions between the transferring receptor (TfR) and transferrin (Tf) and the TfR and the hemochromatosis gene product regulate iron transport into cells. The long term goal of my research is to understand the structure and function of this important receptor. The uptake of iron into mammalian cells involves the binding of Tf to the TfR, followed by internalization of the receptor-Tf complex. Iron uptake is essential for cell division and as a result the TfR has been identified as a proliferation specific marker. It is present on rapidly dividing cells. The uptake of iron into the body and into cells is tightly controlled. Too little iron in mammals results in anemia and failure to thrive. Too much iron results in iron toxicity due to oxidative damage. Hereditary hemochromatosis is a disease of iron overload. Excess iron damages organs and results in liver failure, adult onset diabetes, arthritis and heart failure. It is the most common inherited disease in people of European descent affecting approximately 1 in 400 individuals. Recently the gene was identified and found to bind to the TfR. Key to understanding the regulation of iron uptake is understanding the interactions between the hemochromatosis gene product and between Tf and the TfR. The specific goals of this study application are: to map the interactions between these proteins; to determine how the TfR potentiates the release of iron in the endosome; to determine how the hemochromatosis gene product alters the interaction between Tf and the TfR; and finally to determine the limiting factors in the uptake of iron into cells.