Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins.
Adaptive responses associated with environmental stressors are critical to cell survival. Under conditions when cellular redox and antioxidant defenses are overwhelmed, the selective oxidation of critical methionines within selected protein sensors functions to down-regulate energy metabolism and the further generation of reactive oxygen species (ROS). Mechanistically, these functional changes within protein sensors take advantage of the helix-breaking character of methionine sulfoxide. The sensitivity of several calcium regulatory proteins to oxidative modification provides cellular sensors that link oxidative stress to cellular response and recovery. Calmodulin (CaM) is one such critical calcium regulatory protein, which is functionally sensitive to methionine oxidation. Helix destabilization resulting from the oxidation of either Met(144) or Met(145) results in the nonproductive association between CaM and target proteins. The ability of oxidized CaM to stabilize its target proteins in an inhibited state with an affinity similar to that of native (unoxidized) CaM permits this central regulatory protein to function as a cellular rheostat that down-regulates energy metabolism in response to oxidative stress. Likewise, oxidation of a methionine within a critical switch region of the regulatory protein phospholamban is expected to destabilize the phosphorylation-dependent helix formation necessary for the release of enzyme inhibition, resulting in a down-regulation of the Ca-ATPase in response to beta-adrenergic signaling in the heart. We suggest that under acute conditions, such as inflammation or ischemia, these types of mechanisms ensure minimal nonspecific cellular damage, allowing for rapid restoration of cellular function through repair of oxidized methionines by methionine sulfoxide reductases and degradation pathways after restoration of normal cellular redox conditions.
Bigelow
Diana J
DJ
Cell Biology and Biochemistry Group, Biological Sciences Division; Fundamental Sciences Directorate, Pacific Northwest National Laboratory, P. O. Box 999, Richland, WA 99352, USA.
Squier
Thomas C
TC
D000375:Aging / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D015398:Signal Transduction
D002147:Calmodulin; D008715:Methionine; D000252:Calcium-Transporting ATPases; D002118:Calcium