Widespread occurrence of covalent lysine–cysteine redox switches in proteins

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.

Structural Features of Clostridium botulinum Neurotoxin Subtype A2 Cell Binding Domain

“…A similar observation was made in the structure of H C /A5 involving equivalent residues [ 27 ]. The Lys-X-Cys bridge is a recently reported interaction that may be a widespread phenomenon in many protein structures [ 32 , 33 ]. There are two possible bridging atoms where X is either an O or a C (as a methylene group, CH 2 ).…”

“…Further, a recent report based on a systematic study on the presence of Lys-Cys bridges in protein structures revealed that oxygen is the most likely bridging atom [ 33 ]; therefore, we modelled this atom in the final deposited coordinates.…”

Denaturation resistant P2 tetramer is required to import fatty acids into intraerythrocytic Plasmodium falciparum

“…Neisseria gonorrhoeae (Ng) P2 ortholog exists at the bacterial cell surface and is implicated in host cell invasion (30). In Ng, Lysine-O-Cysteine (NOS) covalent bond mediated redox switch is one of the key regulators in many enzymatic activity (40,41). The widespread occurrence of NOS bond in many enzymes across eukaryotic species depicts its essentiality in the regulation of enzyme activity in general (40,41) .…”

“…In Ng, Lysine-O-Cysteine (NOS) covalent bond mediated redox switch is one of the key regulators in many enzymatic activity (40,41). The widespread occurrence of NOS bond in many enzymes across eukaryotic species depicts its essentiality in the regulation of enzyme activity in general (40,41) . Free radicals in LAFS might mediate NOS bond formation amongst four P2 molecules (41)(42)(43) hence we hypothesized that denaturation resistant PfP2 tetramer might be assembled by NOS cova-lent linkages where Lysine and cysteine residues in four P2 molecules are directly involved.…”

Redox regulation of the SARS-CoV-2 main protease provides new opportunities for drug design

“…Although M pro resides in the cytoplasm, which is typically considered to be of reducing nature, it has been established that oxidative bursts or even physiological redox signaling based on enzymatic production of reactive oxygen species (ROS) such as H 2 O 2 leads to local oxidizing conditions and subsequent oxidation of protein thiols in the cytosol ( 23 ). We recently reported the discovery of lysine-cysteine redox switches in proteins consisting of NOS (nitrogen-oxygen-sulfur) and SONOS (sulfur-oxygen-nitrogen-oxygen-sulfur) bridges ( 24,25 ). Interestingly, M pro is amongst this class of proteins suggesting the possibility that it is redox regulated.…”