Zinc transporters and their functional integration in mammalian cells.
Zinc transporters and their functional integration in mammalian cells.
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DOI：
10.1016/j.jbc.2021.100320
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Fu D
中科院分区：
文献类型：
--
作者：
Kambe T;Taylor KM;Fu D
锌是所有生物体中普遍存在的一种生物金属。细胞内锌的时空动态提供了重要的细胞信号传导机会，但也挑战了细胞内锌的稳态，具有广泛的疾病意义。锌转运蛋白在调节细胞锌平衡和亚细胞锌分布中起核心作用。20世纪90年代中期，哺乳动物锌转运蛋白的两个互补家族（ZnTs和ZIPs）的发现激发了人们对其金属选择性和细胞功能的大量猜测。经过二十年的研究，我们已经得到了锌运输的生化描述。然而，哺乳动物锌转运蛋白在体外的功能与在活细胞中的功能根本不同，在活细胞中，哺乳动物锌转运蛋白被定向到特定的亚细胞位置，参与专门的大分子机制，并与多种细胞过程相关。因此，单个锌转运体的分子功能被重塑并深度整合到细胞中，以促进锌化学的利用来进行酶促反应，调节细胞对病理生理信号的反应，并维护细胞的稳态。目前，驱动哺乳动物锌转运蛋白功能整合的潜在机制在很大程度上是未知的。这种知识差距促使研究重点从纯化锌转运体的体外研究转向哺乳动物锌转运体在亚细胞位置和蛋白质相互作用背景下的细胞研究。在这篇综述中，我们将概述锌转运蛋白的知识是如何从试管中积累到细胞内研究的，突出了我们对哺乳动物锌转运蛋白功能的分子和细胞基础的理解的新见解和范式转变。
Zinc is a ubiquitous biological metal in all living organisms. The spatiotemporal zinc dynamics in cells provide crucial cellular signaling opportunities, but also challenges for intracellular zinc homeostasis with broad disease implications. Zinc transporters play a central role in regulating cellular zinc balance and subcellular zinc distributions. The discoveries of two complementary families of mammalian zinc transporters (ZnTs and ZIPs) in the mid-1990s spurred much speculation on their metal selectivity and cellular functions. After two decades of research, we have arrived at a biochemical description of zinc transport. However, in vitro functions are fundamentally different from those in living cells, where mammalian zinc transporters are directed to specific subcellular locations, engaged in dedicated macromolecular machineries, and connected with diverse cellular processes. Hence, the molecular functions of individual zinc transporters are reshaped and deeply integrated in cells to promote the utilization of zinc chemistry to perform enzymatic reactions, tune cellular responsiveness to pathophysiologic signals, and safeguard cellular homeostasis. At present, the underlying mechanisms driving the functional integration of mammalian zinc transporters are largely unknown. This knowledge gap has motivated a shift of the research focus from in vitro studies of purified zinc transporters to in cell studies of mammalian zinc transporters in the context of their subcellular locations and protein interactions. In this review, we will outline how knowledge of zinc transporters has been accumulated from in-test-tube to in-cell studies, highlighting new insights and paradigm shifts in our understanding of the molecular and cellular basis of mammalian zinc transporter functions.
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