Integrated analysis of the redoxome and zinc proteome links ribosomal protein oxidation to zinc homeostasis.

Abstract

Zinc is an essential trace mineral for human health. However, consuming large amounts of zinc can be toxic. Therefore, zinc homeostasis must be actively regulated. Within cells, zinc mostly exists in a form bound with proteins. We show that the existence of zinc-binding proteins is a conserved feature of kingdoms of life, emphasizing the fundamental importance of zinc in biological systems. Cysteine residues chemically coordinate zinc binding within proteins and are highly sensitive to oxidative modifications under conditions of oxidative stress and aging. This study uses available datasets that analyzed the redoxome and combines this information with zinc-binding annotations. Our analysis reveals that zinc-binding cysteine residues are significant targets of reversible protein oxidation. In particular, we identified proteins of the cytosolic ribosome as zinc-binding oxidation targets during aging. We integrated our findings with data on changes in protein abundance under conditions of low zinc bioavailability. These analyses revealed that ribosomal proteins that bind zinc and are targets of oxidative modifications tend to be less abundant under zinc-depletion conditions. Additionally, the molecular dynamics simulations allowed us to link reversible oxidation of ribosomal proteins to zinc removal from these proteins and their following unfolding in zinc-deficient conditions. Thus, these findings open new possibilities for regulating zinc homeostasis during aging.