Opus22
Structure and role of copper-zinc metallothioneins in the cellular buffering of copper and zinc ions
Project number: 2021/43/B/NZ1/02961
PI: prof. Artur Krężęl
The Biological Role of Metallothioneins
Metallothioneins (MTs) are a family of small, sulfur-rich proteins that bind metal ions. This family consists of structurally similar proteins found in all cells, although with varying preferences. MTs were first discovered in 1957 as molecules that bind cadmium—a toxic element with no essential role in mammals. For many years, MTs were considered primarily as detoxifying agents for cadmium and other harmful metal ions. However, further research revealed that their natural role is to bind zinc, and heavy metals merely displace zinc under exposure conditions. Zinc binding by MTs occurs differently than in other zinc-binding proteins—up to seven metal ions can be bound with varying affinities. This enables MTs to act as cellular buffers: they can release zinc to other proteins when needed or sequester excess zinc.
Copper Binding and Research Objectives
Recent studies have shown that MTs also bind copper, although the function of these proteins in relation to copper remains unclear. Previous research on copper-MT interactions has been conducted mostly in homogeneous systems, focusing solely on copper binding. However, increasing evidence suggests that the natural form of copper bound to MTs involves mixed complexes containing both zinc and copper. So far, no one has described the formation, properties, or functions of these complexes. Given MTs’ role in zinc homeostasis, it is highly probable that copper binding also serves a regulatory function. Studying these mixed complexes is technically challenging due to the reactivity of MTs, copper ions, and the presence of zinc. The main goal of this project is to describe the formation of copper-MT complexes, especially mixed complexes with zinc. Structural studies using mass spectrometry—currently the only method with sufficient resolution—will be crucial. The project aims to determine the number of preferentially formed mixed complexes, the affinity of zinc and copper ions, and their buffering properties. We will test metal transfer between mixed complexes and proteins or motifs that naturally bind zinc and copper in cells. This will help clarify the role of mixed complexes and how these elements are regulated. Furthermore, we will investigate whether the regulation of one metal occurs synergistically with the other.
