Lysine-cysteine redox switches in proteins

Kai Tittmann

Kai Tittmann

Disulfide bonds between cysteine residues are important post-translational modifications in proteins with critical roles for protein structure and stability, as redox-active catalytic groups in enzymes or allosteric redox switches that govern protein function. Regulatory redox switches between two amino acids other than disulfides have not been demonstrated. We recently discovered a crosslink between a cysteine and a lysine with an unprecedented N-O-S bridge that serves as an allosteric redox switch in the enzyme transaldolase from N. gonorrhoeae. High resolution protein crystallography of the protein in the oxidized and reduced state reveals a loaded-spring mechanism with a structural relaxation upon redox activation that is propagated from the allosteric redox switch at the protein surface to the active site. A survey of the protein structure data base discloses that the NOS bridge is existing in diverse protein families across all domains of life. NOS redox switches are found in diverse structural motifs and chemical variants. In several instances, lysines are observed in simultaneous linkage with two cysteines forming a SONOS bridge with a trivalent nitrogen, which constitutes an unusual native branching crosslink. In many proteins, the NOS switch contains a functionally essential lysine with direct roles in enzyme catalysis or binding of substrates, DNA or effectors, linking lysine chemistry and redox biology as a regulatory principle. NOS/SONOS switches are frequently found in proteins from human and plant pathogens including SARS-CoV-2 but also in many human proteins with established roles in gene expression, redox signaling and homeostasis in physiological and pathophysiological conditions.

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