Review
Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins

https://doi.org/10.1016/j.bbapap.2004.09.012Get rights and content

Abstract

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 Met144 or Met145 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 β-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.

Section snippets

Linkages between oxidative stress and energy metabolism: identification of control points

The identification of oxidatively sensitive proteins that modulate energy utilization and the associated generation of reactive oxygen species (ROS) are critical to understanding how cells respond to oxidative stress. In this latter respect, oxidant-induced functional losses of the calcium regulatory proteins calmodulin (CaM) and the sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) contribute to the down-regulation of cellular metabolism and ATP utilization and the associated generation of

Aging, metabolic rate, and adaptive cellular responses

Biological aging represents a chronic oxidative stress that initiates a series of adaptive cellular responses. Understanding these control mechanisms, which permit optimal cell function and the management of oxidative stress, is critical to an appreciation of cellular stress responses. In this respect, caloric restriction results in an enhanced life span that correlates with the differential expression of critical proteins involved in energy metabolism, stress responses, and calcium regulation

Calcium regulatory proteins and linkages to energy metabolism

Calcium functions as a critical second messenger in mediating fast intracellular responses in all eukaryotic tissues through the activation of CaM and other signaling proteins to coordinate cell function with energy metabolism. In addition, calcium mediates adaptive responses through the direct modulation of numerous transcription factors, including Nrf2, NFAT, and NF-κB family members c-Rel and RelA [6], [7], [8], [9]. The sequence of events that modulates cell function involves the feedback

Functional targets of oxidation during aging

The selective and reversible oxidation of critical sites within proteins involved in signal transduction cascades would suggest a regulatory function analogous to previously recognized mechanisms involving protein phosphorylation. It is, therefore, important to consider the extent of protein modifications that occurs under conditions of oxidative stress. Approximately one-half of intracellular proteins are oxidized in senescent animals, suggesting that during aging there is a nonselective

Calmodulin and mechanisms underlying inhibitory action of methionine oxidation

CaM functions to interpret the calcium signal in all cells, and coordinates energy metabolism involving the mobilization of cellular energy reserves with gene transcriptional regulation through the differential activation of over 50 different target proteins (Fig. 2) [10]. Thus, modulation of the cellular concentration of CaM directly affects cellular function through the differential activation of low-affinity target proteins. This regulation follows from the observation that under all

Nitration as an indicator of peroxynitrite: a potent oxidant of methionines

Peroxynitrite (ONOO−), formed from the spontaneous combination of nitric oxide (NOradical dot) and superoxide (O2−), is among the most common physiological oxidants [63], [64]. The near diffusion-controlled rate of this reaction competes effectively with removal of superoxide by SOD, with the effect that ONOO− formation occurs when cellular nitric oxide levels are comparable to those of SOD (i.e., micromolar). Diffusive and capable of rapidly crossing lipid membranes, peroxynitrite is highly reactive

Phospholamban and Ca-ATPase inhibition: linkage between methionine oxidation and calcium uptake

A recent proteomic screen of phosphoproteins has revealed the oxidation of Met20 within phospholamban in nonfailing human heart following trauma, consistent with the presence of an oxidative/nitrative stress in the heart by peroxynitrite (Fig. 6) [87]. This observation also raises the intriguing question regarding what functional significance this oxidation may have on phospholamban regulation of SERCA2a and its possible role as an alternate sensor of cellular stress. Certain predictions can be

Methionine oxidation functions as a conformational switch

The sensitivity of methionines to oxidation, coupled with large differences in the helix-promoting abilities of methionine and the resulting methionine sulfoxide, permits their use as sensors of oxidative stress to serve as conformational switches that modulate the activity of central regulatory proteins (i.e., Ca-ATPase and the regulatory proteins phospholamban and CaM) (Fig. 8). These conformational switches are directly coupled to cellular redox conditions through the actions of methionine

Acknowledgements

This work was supported by grants AG12993, AG18013 and AG17996 from the National Institutes of Health.

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