Post-Translational Regulation of Superoxide Dismutase 1 (SOD1): The Effect of K122 Acylation on SOD1's Metabolic Activity
Many mutations in superoxide dismutase 1 (SOD1) cause destabilization and misfolding of the protein and are implicated in amyotrophic lateral sclerosis. Likewise, a few post-translational modifications (PTMs) on SOD1 have been shown to cause the same phenotype. However, relatively few PTMs on SOD1 h...
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| Format: | Others |
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BYU ScholarsArchive
2017
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| Online Access: | https://scholarsarchive.byu.edu/etd/6941 https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=7941&context=etd |
| Summary: | Many mutations in superoxide dismutase 1 (SOD1) cause destabilization and misfolding of the protein and are implicated in amyotrophic lateral sclerosis. Likewise, a few post-translational modifications (PTMs) on SOD1 have been shown to cause the same phenotype. However, relatively few PTMs on SOD1 have been studied in depth and, in particular, very few studies have demonstrated how these PTMs affect SOD1's various biological roles. SOD1 is traditionally known for its role in reactive oxygen species (ROS)-scavenging but has also been found to have a few other biological roles, including transcription factor activity to promote genomic stability, preservation of cytoskeletal activity, maintaining zinc and copper homeostasis, and suppressing respiration. We have used the computational analysis tool, SAPH-ire, to find PTM 'hotspots' on SOD1 that have a high likelihood of affecting its biological functions. Interestingly, the top seven ranked PTM 'hotspots' were found in a small region of SOD1, between S98-K128. We focused our studies on one of the PTM 'hotspots' found in this region, lysine-122 (K122). K122 is found in the electrostatic loop of SOD1, a loop that is important for shuttling in superoxide radicals to be neutralized. According to our data, and other studies, this lysine is both succinylated and acetylated. We found that acetyl and succinyl-mimetics (K122Q and K122E, respectively) of this site do not affect its ROS scavenging activity but do prevent SOD1 from suppressing respiration and decrease its localization to the mitochondria. Further, when cells are depleted of SIRT5 (the desuccinylase for K122), SOD1 can no longer suppress respiration. Additionally, we found that SOD1 appears to suppress respiration at complex I, whether directly or through an indirect pathway is unknown. When HCT116 colon cancer cells were depleted of endogenous SOD1, the overexpressed succinyl K122-mimetic (K122E) could not recover growth as well as overexpressed WT SOD1. The K122E SOD1 expressing cells also exhibited increased mitochondrial ROS and unhealthier mitochondria. We propose a mechanism whereby SOD1 suppression of respiration acts as an additional regulator of oxidative stress: SOD1 suppresses the electron transport chain to decrease reactive oxygen species leakage and to promote healthier mitochondria and growth. |
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