MECHANISMS OF CELLULAR IRON UPTAKE FROM TRANSFERRIN

尽管近年来对铁代谢的认识有了长足的进步，但对哺乳动物细胞中铁的运输和动态平衡的调节仍未被发现。目前的研究集中在转铁蛋白和转铁蛋白受体在管理铁向铁依赖细胞输送中的作用。本文介绍了两项合作努力，其中一项基本上是自给自足的。在第一个研究中，主要是与该计划的项目2合作研究，重点是转铁蛋白受体的转铁蛋白识别位点。铁需求细胞的转铁蛋白受体不仅具有结合和内化转铁蛋白的功能，而且还调节转铁蛋白释放铁的功能。我们的目标是确定受体如何识别和结合转铁蛋白，受体-转铁蛋白复合体如何抵抗其内化的酸化内体内的破坏，以及受体如何以pH依赖的方式调节转铁蛋白释放铁。接下来，在我们的主要工作中，我们试图通过确保转铁蛋白携带的铁的转移来了解肝细胞表现出的受体非依赖性途径中的分子事件。这种途径可能比更好地理解和更经常研究的受体介导的途径为肝细胞获得更多的铁。在我们的第三项工作中，与该计划的项目5共同努力，我们将探索伴随着转铁蛋白结合和释放铁的构象变化。在这里，我们的目的是解开转铁蛋白构象变化的序列和机制。在这里，我们的目标是揭开转铁蛋白构象变化的序列和机制。我们的方法是以问题为导向，结合细胞生物学、分子生物学(诱变)和物理生物化学的方法，以获得有关铁代谢的基本生物学过程的信息。

Although recent years have seen tremendous strides in the understanding of iron metabolism, which remains to be uncovered about the regulation of iron transport and homeostasis in mammalian cells. The present study focuses on the roles of transferrin and the transferrin receptor in managing the delivery of iron to iron-dependent cells. Two collaborative efforts, and one that is largely self-contained, are presented. In the first of these, a largely collaborative study with Project 2 of the Program, the emphasis is on the transferrin-recognition site of the transferrin receptor. The transferrin receptor of iron-requiring cells functions not only to bind and internalize transferrin, but also to modulate iron release from transferrin. Our goal is to determine how the receptor recognizes and binds transferrin, how the receptor-transferrin complex resists disruption within the acidified endosome to which it is internalized, and how the receptor regulates iron release from transferrin in a pH-dependent fashion. Next, in our major undertaking, we seek to understand the molecular events in the receptor-independent pathway exhibited by hepatic cells by securing transferring transferrin- borne iron. This pathways may secure more iron for hepatocytes than the much better understood, and more often studied, receptor-mediated route. In our third undertaking, a joint effort with Project 5 of the Program, we will explore the conformational changes accompanying the binding and release of iron by transferrin. Here, our aim is to unravel the sequences and mechanisms of conformational changes in transferrin. Here, our aim is to unravel the sequences and mechanisms of conformational changes in transferrin Our approach is problem-oriented and multi- disciplinary combining methods of cell biology, molecular biology (mutagenesis), and physical biochemistry to gain information into the fundamental biological processes of iron metabolism.