Abstract
We recently reported the discovery of a lysine–cysteine redox switch in proteins with a covalent nitrogen–oxygen–sulfur (NOS) bridge. Here, a systematic survey of the whole protein structure database discloses that NOS bridges are ubiquitous redox switches in proteins of all domains of life and are found in diverse structural motifs and chemical variants. In several instances, lysines are observed in simultaneous linkage with two cysteines, forming a sulfur–oxygen–nitrogen–oxygen–sulfur (SONOS) bridge with a trivalent nitrogen, which constitutes an unusual native branching cross-link. 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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and also in many human proteins with established roles in gene expression, redox signaling and homeostasis in physiological and pathophysiological conditions.
Highlights
Reactive oxygen species (ROS) are central to redox signaling in all domains of life and critically control cell growth, development, metabolism, aging and the response to stress conditions, such as, for example, infection by pathogens[1,2,3,4]
Before we analyzed the deposited experimental protein structures in the protein database to search for potentially undetected covalent NOS bridges, we sought to define the geometric properties of covalent NOS bridges versus non-covalent hydrogen-bond interactions between cysteine and lysine residues to identify reliable criteria to discern between these scenarios
A survey of hydrogen-bond interactions of cysteines in protein structures disclosed mean interatomic S–N distances of 3.44 Å with lysine residues and 3.75 Å when cysteine acts as a hydrogen-bond donor[10]
Summary
Reactive oxygen species (ROS) are central to redox signaling in all domains of life and critically control cell growth, development, metabolism, aging and the response to stress conditions, such as, for example, infection by pathogens[1,2,3,4]. We systematically mine the available protein structure database for proteins with undetected lysine–cysteine cross-links and find hitherto unidentified NOS bridges in proteins from all domains of life with critical roles in central cellular functions, including metabolism, gene expression, signaling, the ubiquitin pathway, DNA repair and redox homeostasis. These findings have wide-ranging biological implications in the context of redox signaling, oxidative stress and many human disease states
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