Cysteine-based biomolecules regulate cellular copper- and redox-homeostasis

Homeostasis, a balance state in cells, is crucial for proper cellular function, growth, and long-term survival. Otherwise, imbalanced homeostasis fosters many diseases. Specifically, cysteine (Cys)-based biomolecules are involved in cellular homeostasis. A group of Cys-based proteins called Cu-chaperons properly distributes and excretes excess Cu by exchanging Cu and cysteine ligands with partner proteins according to their affinity gradient, thus maintaining a balance of cellular Cu. Other groups of Cys-based proteins act as redox switches, especially, “glutathione systems” (glutathione, glutathione peroxidases, glutaredoxins, and glutathione reductase) and “thioredoxin systems” (thioredoxin, and thioredoxin reductase) that detoxify the reactive oxygen species (ROS) or oxidative damaged biomolecules to control the cellular redox balance through a reversible thiol-disulfide exchange, which is the central redox hub for cellular redox homeostasis. Moreover, Cu-homeostasis is linked to the redox system and both may synergistically balance the cellular Cu and redox. Therefore, this review brings attention to two important roles of Cys-based proteins: cellular copper-homeostasis and redox-homeostasis, wherein structures and mechanisms of Cu-trafficking and redox regulation, followed by a close relationship between Cu-chaperons and cellular redox systems, and different functions/redox potentials of the same Cys motif (CXXC) in various proteins are considered.