A lysine–cysteine redox switch with an NOS bridge regulates enzyme function

Marie Wensien, Fabian Rabe Pappenheim, Lisa-Marie Funk, Patrick Kloskowski, Ute Curth, Ulf Diederichsen, Jon Uranga, Jin Ye, Pan Fang, Kuan-Ting Pan, Henning Urlaub, Ricardo A. Mata, Viktor Sautner and Kai Tittmann ()
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Marie Wensien: Georg August University Göttingen
Fabian Rabe Pappenheim: Georg August University Göttingen
Lisa-Marie Funk: Georg August University Göttingen
Patrick Kloskowski: Georg August University Göttingen
Ute Curth: Hannover Medical School
Ulf Diederichsen: Georg August University Göttingen
Jon Uranga: Georg August University Göttingen
Jin Ye: Georg August University Göttingen
Pan Fang: Max Planck Institute for Biophysical Chemistry
Kuan-Ting Pan: Max Planck Institute for Biophysical Chemistry
Henning Urlaub: Max Planck Institute for Biophysical Chemistry
Ricardo A. Mata: Georg August University Göttingen
Viktor Sautner: Georg August University Göttingen
Kai Tittmann: Georg August University Göttingen

Nature, 2021, vol. 593, issue 7859, 460-464

Abstract: Abstract Disulfide bonds between cysteine residues are important post-translational modifications in proteins that have critical roles for protein structure and stability, as redox-active catalytic groups in enzymes or allosteric redox switches that govern protein function1–4. In addition to forming disulfide bridges, cysteine residues are susceptible to oxidation by reactive oxygen species, and are thus central not only to the scavenging of these but also to cellular signalling and communication in biological as well as pathological contexts5,6. Oxidized cysteine species are highly reactive and may form covalent conjugates with, for example, tyrosines in the active sites of some redox enzymes7,8. However, to our knowledge, regulatory switches with covalent crosslinks other than disulfides have not previously been demonstrated. Here we report the discovery of a covalent crosslink between a cysteine and a lysine residue with a NOS bridge that serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae, the pathogen that causes gonorrhoea. X-ray structure analysis of the protein in the oxidized and reduced state reveals a loaded-spring mechanism that involves a structural relaxation upon redox activation, which is propagated from the allosteric redox switch at the protein surface to the active site in the protein interior. This relaxation leads to a reconfiguration of key catalytic residues and elicits an increase in enzymatic activity of several orders of magnitude. The redox switch is highly conserved in related transaldolases from other members of the Neisseriaceae; for example, it is present in the transaldolase of Neisseria meningitides (a pathogen that is the primary cause of meningitis and septicaemia in children). We surveyed the Protein Data Bank and found that the NOS bridge exists in diverse protein families across all domains of life (including Homo sapiens) and that it is often located at catalytic or regulatory hotspots. Our findings will inform strategies for the design of proteins and peptides, as well as the development of new classes of drugs and antibodies that target the lysine–cysteine redox switch9,10.

Date: 2021
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DOI: 10.1038/s41586-021-03513-3

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