10.2 Sensing Oxidative Stress
KEY CONCEPTS
By the end of this section, you will be able to do the following:
- Apply your understanding of cell signalling pathways (Chapter 5.6) and redox reactions (Chapter 6.3) to explain how ROS are involved in normal cell signalling via reversible redox switches.
- Explain why irreversible oxidation of proteins is a good indicator of oxidative stress, and give an example of modifications to cysteine that are irreversible.
For a cell to survive oxidative stress, it must be able to detect ROS. Cells can detect ROS levels through redox signaling, a form of cellular communication that involves the reversible oxidation of amino acids in receptor proteins. If you need to review the basics of cell signalling, refer back to Chapter 5.6.
Reversible Oxidation of Receptor Proteins
As described above (Chapter 10.1), ROS can covalently modify proteins, for example by oxidizing amino acids like cysteine (Figure 10.4). If these modifications occur on a receptor protein in a redox signalling pathway, the resulting change in structure in the receptor protein can activate that signalling pathway (Figure 10.5). This method of activating a receptor protein is different from most signalling molecules (ligands), which reversibly (and non-covalently) bind to their receptor protein (Chapter 5.6). However, ROS modifications to redox receptor proteins are also usually reversible – the oxidized amino acids can be reduced (Figure 10.5) to deactivate the redox receptor protein and its signalling pathway(s). Thus, redox reactions involving amino acids in a receptor protein can act as a “switch” that either activates or deactivates signalling pathways in the presence of ROS. For ROS to act as specific signalling molecules, they are often produced in close proximity to their target receptor proteins. This is often essential because ROS can modify any protein they come in contact with, not just redox signalling proteins.
Hydrogen peroxide is thought to be the most involved ROS in cell signaling because it is the most stable and is nonpolar, allowing it to diffuse through cellular membranes. H2O2 oxidizes its target protein, cysteine residues. One common reaction is for H2O2 to convert the thiol (SH) group on cysteine into sulfenic acid (SOH; Figure 10.5). This amino acid modification can change the shape of the protein and thus its function. This oxidized protein may change its activity, location in the cell, or ability to bind to other proteins (Figure 10.5), stimulating changes in a cell signalling pathway. Through a reduction reaction, the sulfenic acid group can return to a thiol group, allowing the protein to return to its original shape and function. This example demonstrates that some redox reactions are reversible (Figure 10.5).
Irreversible Oxidation of Receptor Proteins
During oxidative stress there is an increase in ROS, which can cause above-normal levels of amino acid oxidation in proteins. These oxidation reactions can be irreversible. For example, sulfenic acid groups on cysteine can be converted to sulfinic acid (SO2H) or sulfonic acid (SO3H), as seen in Figure 10.5. These irreversible modifications to redox receptor proteins are a signal to the cell that ROS levels have exceeded normal concentrations. If there is a high concentration of ROS in a properly functioning cell, a homeostatic feedback system is enabled to increase the concentration antioxidants to help return ROS concentration to an appropriate, non-toxic level. If oxidative stress continues to a point where a lot of damage occurs, cells also have mechanisms to detect this damage, as described further in Chapter 14.
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