Krężel Artur, Maret Wolfgang
Department of Chemical Biology, Faculty of Biotechnology, University of Wrocław, Wrocław 50-383, Poland.
Departments of Biochemistry and Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, U.K.
Chem Rev. 2021 Dec 8;121(23):14594-14648. doi: 10.1021/acs.chemrev.1c00371. Epub 2021 Oct 15.
The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. They exist in multiple forms with different degrees of metalation and types of metal ions. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn(II) and Cu(I) ions in cellular space and time.
自60多年前发现金属硫蛋白以来，其功能、目的和作用一直是人们猜测的对象。本文梳理了研究历史，并通过对结构 - 稳定性 - 功能关系提供新的解释来解决多个争议。它挑战了一种教条，即哺乳动物蛋白质的生物学相关结构仅为由X射线衍射和核磁共振光谱所确定的结构。金属硫蛋白和硫蛋白这两个术语含糊不清，不足以理解其生物学功能。需要在其生物学背景中看待这些蛋白质，这限制并定义了可能的化学性质。它们以多种形式存在，具有不同程度的金属化和金属离子类型。哺乳动物金属硫蛋白的同配硫醇盐配位对其分子机制很重要。它赋予蛋白质氧化还原活性以及其金属亲和力对特定pH的依赖性。因此，这些蛋白质也以硫供体配体的不同氧化还原状态存在。它们的配位动力学允许与其他蛋白质和配体相互作用的广阔构象景观。许多基本的信号转导途径调节着人类十几种金属硫蛋白基因的表达。在理解细胞锌和铜稳态控制方面的最新进展为以下观点奠定了基础，即哺乳动物金属硫蛋白提供了一种高度动态、受调控且独特的生物金属缓冲剂，以控制细胞空间和时间中最具竞争力的Zn(II)和Cu(I)离子的可用性、波动和信号瞬变。
