Protein S-sulfenylation is a fleeting molecular switch that regulates non-enzymatic oxidative folding

Beedle, Amy E. M.; Lynham, Steven; Garcia-Manyes, Sergi

doi:10.1038/ncomms12490

Cited by 57 publications

(44 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Owing to their chemical properties, ROS can modify target proteins, changing their conformation or activity. Reversible redox modifications provide a powerful signaling network, not unlike phosphorylation 88 . For instance, cysteine residues can adopt numerous oxidation states (SS, SOH, SO 2 H, SO 3 H, SNO, SSH etc.…”

Section: Targets Of Oxidative Stress In Mitochondria Peroxisomes Andmentioning

confidence: 99%

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

2018

View full text Add to dashboard Cite

Many cellular redox reactions housed within mitochondria, peroxisomes and the endoplasmic reticulum (ER) generate hydrogen peroxide (H2O2) and other reactive oxygen species (ROS). The contribution of each organelle to the total cellular ROS production is considerable, but varies between cell types and also over time. Redox-regulatory enzymes are thought to assemble at a “redox triangle” formed by mitochondria, peroxisomes and the ER, assembling “redoxosomes” that sense ROS accumulations and redox imbalances. The redoxosome enzymes use ROS, potentially toxic by-products made by some redoxosome members themselves, to transmit inter-compartmental signals via chemical modifications of downstream proteins and lipids. Interestingly, important components of the redoxosome are ER chaperones and oxidoreductases, identifying ER oxidative protein folding as a key ROS producer and controller of the tri-organellar membrane contact sites (MCS) formed at the redox triangle. At these MCS, ROS accumulations could directly facilitate inter-organellar signal transmission, using ROS transporters. In addition, ROS influence the flux of Ca2+ ions, since many Ca2+ handling proteins, including inositol 1,4,5 trisphosphate receptors (IP3Rs), SERCA pumps or regulators of the mitochondrial Ca2+ uniporter (MCU) are redox-sensitive. Fine-tuning of these redox and ion signaling pathways might be difficult in older organisms, suggesting a dysfunctional redox triangle may accompany the aging process.

show abstract

Section: Targets Of Oxidative Stress In Mitochondria Peroxisomes Andmentioning

confidence: 99%

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

2018

View full text Add to dashboard Cite

show abstract

“…For example, reactants such as glutathione and hydroxide can react with cryptic cysteine residues to block protein folding. [8] However, in contrast to oxidative ageing which is irreversible, such thiol modifications are fully reversible and are part of healthy cellular homeostasis.…”

mentioning

confidence: 99%

Mechanical Deformation Accelerates Protein Ageing

et al. 2017

View full text Add to dashboard Cite

A hallmark of tissue ageing is the irreversible oxidative modifications of its constituent proteins. We show that single proteins, kept unfolded and extended by a mechanical force, undergo accelerated ageing in times scales of minutes to days. A protein forced to be continuously unfolded loses completely its ability to contract by folding, becoming a labile polymer. Ageing rates vary among different proteins, but in all cases they lose their mechanical integrity. Random oxidative modification of cryptic side chains exposed by mechanical unfolding can be slowed by the addition of antioxidants such as ascorbic acid, or accelerated by oxidants. By contrast, proteins kept in the folded state and probed over week-long experiments show greatly reduced rates of ageing. We demonstrate a novel assay where protein ageing can be greatly accelerated: the constant unfolding of a protein for hours to days is equivalent to decades of exposure to free radicals under physiological conditions.

show abstract

“…Our approach provides an extra level of understanding on the molecular mechanisms of disulfide bond reformation under force, and its direct link to mechanical folding. Crucially, our measurements reflect the largely distinct role of the closely related S-cysteinylation and S-homocysteinylation on protein elasticity, and add to the emerging research field that highlights the importance of force-induced exposure of cryptic sites to regulate protein nanomechanics, both via post-translational modifications, such as S-glutathionylation12 and S-sulfenylation13, or through the unravelling of metal binding sites71. More generally, our proof-of-principle approach demonstrates the use of highly localized chemical reactivity—which can be potentially expanded to other distinct chemical mechanisms—to rationally tailor protein elasticity, and offer a new approach to engineer reversible redox-responsive protein-based biomaterials with adaptable mechanical properties.…”

Section: Discussionmentioning

confidence: 69%

Tailoring protein nanomechanics with chemical reactivity

et al. 2017

Self Cite

View full text Add to dashboard Cite

The nanomechanical properties of elastomeric proteins determine the elasticity of a variety of tissues. A widespread natural tactic to regulate protein extensibility lies in the presence of covalent disulfide bonds, which significantly enhance protein stiffness. The prevalent in vivo strategy to form disulfide bonds requires the presence of dedicated enzymes. Here we propose an alternative chemical route to promote non-enzymatic oxidative protein folding via disulfide isomerization based on naturally occurring small molecules. Using single-molecule force-clamp spectroscopy, supported by DFT calculations and mass spectrometry measurements, we demonstrate that subtle changes in the chemical structure of a transient mixed-disulfide intermediate adduct between a protein cysteine and an attacking low molecular-weight thiol have a dramatic effect on the protein's mechanical stability. This approach provides a general tool to rationalize the dynamics of S-thiolation and its role in modulating protein nanomechanics, offering molecular insights on how chemical reactivity regulates protein elasticity.

show abstract

Protein S-sulfenylation is a fleeting molecular switch that regulates non-enzymatic oxidative folding

Cited by 57 publications

References 69 publications

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

Mechanical Deformation Accelerates Protein Ageing

Tailoring protein nanomechanics with chemical reactivity

Contact Info

Product

Resources

About