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

Wensien, Marie; Pappenheim, Fabian Rabe von; Funk, Lisa-Marie; Kloskowski, Patrick; Curth, Ute; Diederichsen, Ulf; Uranga, Jon; Ye, Jin; Pan, Fang; Pan, Kuan-Ting; Urlaub, Henning; Mata, Ricardo A.; Sautner, V.; Tittmann, Kai

doi:10.1038/s41586-021-03513-3

Cited by 94 publications

(131 citation statements)

References 56 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…In sum, to reliably detect NOS bridges in protein crystal structures, a resolution of better than 2 Å is required as well as a high occupancy of this group and sufficient local order. "Radiation damage" can be excluded to cause NOS bridge formation artificially as we have demonstrated before 9 , to the contrary, NOS bridges decompose while interacting with high-energy radiation but only at very high doses.…”

Section: Detectability Of Nos Bridges In Crystallographic Protein Structuresmentioning

confidence: 70%

“…We remodeled both residues with a covalent crosslink, either as an NOS bridge, or, alternatively, as a direct N-S linkage (sulfenamide) using geometrically parametrized restraints. We consider formation of a methylene (N-CH2-S) bridge as highly unlikely as previously discussed by us and others 9,13 . We then re-refined the structures and compared the obtained models and electron density maps for the three alternative scenarios: i) a covalent NOS linkage, ii) a covalent N-S linkage and iii) a non-covalent H-bond interaction (as deposited).…”

Section: Detectability Of Nos Bridges In Crystallographic Protein Structuresmentioning

confidence: 89%

“…In our initial discovery of the allosteric NOS redox switch in the enzyme transaldolase from Neisseria gonorrhoeae 9 , we had speculated that a neighboring glutamate (Glu93) might be catalytically essential for formation of the NOS bridge akin to the suggested role of a glutamate in isopeptide bond formation in some proteins 20 (ED Fig. 4a).…”

Section: Catalytic Requirements For Nos/sonos Bridge Formationmentioning

confidence: 99%

“…In a next step, we analyzed the chemical functions of the lysine and cysteine residues forming the NOS/SONOS redox switches in the context of the respective protein structure and function. In the previously reported redox-sensitive transaldolase, the NOS bridge functions as an allosteric switch that changes the structure of the protein including that of the active site, and thereby regulates enzymatic activity 9 . The operational modes of the NOS/ SONOS redox switch residues in the now identified proteins are amazingly diverse and can be classified into several major classes including lysines with direct catalytic roles, lysines with direct binding roles, cysteines with direct catalytic roles, and allosteric switches (Fig.…”

Section: Chemical Functions Of the Nos Lysine And Cysteine Residuesmentioning

confidence: 99%

“…We have recently reported the discovery of an allosteric lysine-cysteine redox switch with a covalent NOS bridge that regulates the enzymatic activity in response to changing redox conditions 9 . Here, we systematically mine the available protein structure database for proteins with undetected lysine-cysteine redox switches 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.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

NOS and SONOS redox switches in proteins

Pappenheim

Wensien

Jin

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

We recently reported on the discovery of a lysine-cysteine redox switch in proteins with a covalent NOS bridge. Here, a systematic survey of the whole protein structure database discloses that NOS bridges are ubiquitous, hitherto overlooked 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 SONOS bridge with a trivalent nitrogen, which constitutes the first native branching crosslink in proteins. 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 novel regulatory principle. The NOS/SONOS switches are frequently found in proteins from human and plant pathogens including i.a. SARS-CoV-2 but also in many human proteins with established roles in gene expression, redox signaling and homeostasis in both physiological and pathophysiological conditions. Targeting, mimicking, controlling and engineering the NOS and SONOS redox switches appear to open novel avenues in drug, antiviral, antibiotic and herbicide development, in biocatalytic applications as well as in protein design and bioorganic chemistry.

show abstract

Section: Detectability Of Nos Bridges In Crystallographic Protein Structuresmentioning

confidence: 70%

Section: Detectability Of Nos Bridges In Crystallographic Protein Structuresmentioning

confidence: 89%

Section: Catalytic Requirements For Nos/sonos Bridge Formationmentioning

confidence: 99%

Section: Chemical Functions Of the Nos Lysine And Cysteine Residuesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

NOS and SONOS redox switches in proteins

Pappenheim

Wensien

Jin

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

A Cell‐Permeable Photosensitizer for Selective Proximity Labeling and Crosslinking of Aggregated Proteome

Feng,

Zhao,

Zhao

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Intracellular proteome aggregation is a ubiquitous disease hallmark with its composition associated with pathogenicity. Herein, this work reports on a cell‐permeable photosensitizer (P8, Rose Bengal derivative) for selective photo induced proximity labeling and crosslinking of cellular aggregated proteome. Rose Bengal is identified out of common photosensitizer scaffolds for its unique intrinsic binding affinity to various protein aggregates driven by the hydrophobic effect. Further acetylation permeabilizes Rose Bengal to selectively image, label, and crosslink aggregated proteome in live stressed cells. A combination of photo‐chemical, tandem mass spectrometry, and protein biochemistry characterizations reveals the complexity in photosensitizing pathways (both Type I & II), modification sites and labeling mechanisms. The diverse labeling sites and reaction types result in highly effective enrichment and identification of aggregated proteome. Finally, aggregated proteomics and interaction analyses thereby reveal extensive entangling of proteostasis network components mediated by HSP70 chaperone (HSPA1B) and active participation of autophagy pathway in combating proteasome inhibition. Overall, this work exemplifies the first photo induced proximity labeling and crosslinking method (namely AggID) to profile intracellular aggregated proteome and analyze its interactions.

show abstract

Photo‐regulated synergistic catalysis of acid and basic sites in metal–organic framework

Wen,

Nian,

Tan

et al. 2024

AIChE Journal

View full text Add to dashboard Cite

Enzymes have flexible structures and can modulate the multiple catalytic sites efficiently for synergistic catalysis. Inspired by enzymes, various artificial catalysts have been designed, while controllable synergistic effects in artificial catalysts have never been reported. Here, we report the first example of photo‐regulated synergistic catalyst (PRSC) and the synergistic effects between acidic and basic sites can be regulated by light. PRSCs have acidic sites on pore walls and basic sites on pendant azobenzene groups, and photo‐regulation is achieved through azobenzene isomerization. In the cascade reaction of converting benzaldehyde dimethyl acetal (BA) to benzylidenemalononitrile (BM), the PRSC shows a change of up to 33.6% in BM yield. Mechanism exploration indicates that cis azobenzene makes the catalytic system more stable. The promoted adsorption energy of the reactant malononitrile (MN) on basic sites and the activated C atom of MN that connects to methylene groups are responsible for the tunable synergistic effects of PRSCs.

show abstract

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

Cited by 94 publications

References 56 publications

NOS and SONOS redox switches in proteins

NOS and SONOS redox switches in proteins

A Cell‐Permeable Photosensitizer for Selective Proximity Labeling and Crosslinking of Aggregated Proteome

Photo‐regulated synergistic catalysis of acid and basic sites in metal–organic framework

Contact Info

Product

Resources

About