Disulfide bond formation in the cytoplasm.

SIGNIFICANCE: Disulfide bond formation is critical for biogenesis of many proteins. While most studies in this field are aimed at elucidating the mechanisms in the endoplasmic reticulum, intermembrane space of mitochondria, and prokaryotic periplasm, structural disulfide bond formation also occurs in other compartments including the cytoplasm. Such disulfide bond formation is essential for biogenesis of some viruses, correct epidermis biosynthesis, thermal adaptation of some extremophiles, and efficient recombinant protein production. RECENT ADVANCES: The majority of work in this new field has been reported in the past decade. Within the past few years very significant new data have emerged on the catalytic and noncatalytic mechanisms for disulfide bond formation in the cytoplasm. This includes the crystal structure of a key component of viral oxidative protein folding, identification of a missing component in cytoplasmic disulfide bond formation in hyperthermophiles, and introduction of de novo dithiol oxidants in engineered oxidative folding pathways. CRITICAL ISSUES AND FUTURE DIRECTIONS: While a broad picture of cytoplasmic disulfide bond formation has emerged many critical questions remain unanswered. The individual components in the natural systems are largely known, but the molecular mechanisms by which these processes occur are largely deduced from the mechanisms of analogous components in other compartments. This prevents full understanding and manipulation of these systems, including the potential for novel anti-viral drugs based on the unique features of their sulfhydryl oxidases and the generation of more efficient cell factories for the large-scale production of therapeutic and industrial proteins.