Cell Biology of Cysteine-Based Molecular Switches

Reversible posttranslational protein modifications form the mechanistic basis for the reception and propagation of biological signals in cells. Besides other modifications such as phosphorylation, acetylation, ADP-ribosylation, and ubiquitylation, reduction-oxidation (redox) processes allow reversible structure-function modulation of proteins, which serve as molecular on-off switches in cell biology. Although many protein-bound amino acids and even the peptide backbone can react with oxidizing metabolites during oxidative stress, only three amino acids adopt reversible redox modifications: cysteine, selenocysteine, and methionine. Among these, cysteine-based molecular switches are by far the most prevalent and best studied. Cysteine switches (or " sulfur switches ") respond in heterogeneous, context-dependent manner to a variety of stimuli (endogenous metabolites, chemicals from the diet, xenobiotics, or air oxidants) by direct modification. Common covalent modifications of cysteines include intra-or intermolecular protein-protein disulfide-channel opening. In this special issue, we have attempted to illustrate the versatility of cysteine-based protein regulation and its impact on the physiology of cells and organisms. In both the secretory pathway and the mitochon-drial intermembrane space (IMS), protein maturation often requires the introduction of disulfide crosslinks to promote or maintain protein structure. During this process known as oxidative protein folding, introduced disulfide bridges can be reshuffled, until the native conformation is achieved. Dedicated oxidative folding catalysts, as reviewed by Y. Onda, exist in the endoplasmic reticulum (ER), IMS, and chloroplasts in plant cells as well as in the extracellular space. The disulfide-generating machineries in ER and IMS are conserved in plants, fungi, and animals. Evolutionary and mechanistic aspects of disulfide-bond formation in IMS are discussed by M. Fischer and J. Riemer. Interestingly, the core components of this machinery, Erv1/ALR and Mia40, have additional, poorly understood functions in liver regeneration and hypoxia response, which are likely fulfilled through mechanisms other than oxidative folding in IMS. Two contributions are concerned with the involvement of cysteines in the regulation of antibody secretion and differentiation of B lymphocytes. The review article by T. Anelli and E. van Anken enlightens how cysteine redox status acts as a quality control checkpoint to ensure that only mature IgM antibodies leave the compartments of the early secretory pathway en route to the blood stream. Immature antibodies are tagged with a free cysteine, which is covalently trapped by interchain disulfide formation with the retrieval factor ERp44 at the lowered pH of postER compartments. In this process, the active site cysteine in ERp44 apparently acts as a pH sensor. Antibody …