Post-translational modification by cysteine protects Cu/Zn-superoxide dismutase from oxidative damage.
Reactive oxygen species (ROS) are cytotoxic. To remove ROS, cells have developed ROS-specific defense mechanisms, including the enzyme Cu/Zn superoxide dismutase (SOD1), which catalyzes the disproportionation of superoxide anions into molecular oxygen and hydrogen peroxide. Although hydrogen peroxide is less reactive than superoxide, it is still capable of oxidizing, unfolding, and inactivating SOD1, at least in vitro. To explore the relevance of post-translational modification (PTM) of SOD1, including peroxide-related modifications, SOD1 was purified from postmortem human nervous tissue. As much as half of all purified SOD1 protein contained non-native post-translational modifications (PTMs), the most prevalent modifications being cysteinylation and peroxide-related oxidations. Many PTMs targeted a single reactive SOD1 cysteine, Cys111. An intriguing observation was that unlike native SOD1, cysteinylated SOD1 was not oxidized. To further characterize how cysteinylation may protect SOD1 from oxidation, cysteine-modified SOD1 was prepared in vitro and exposed to peroxide. Cysteinylation conferred nearly complete protection from peroxide-induced oxidation of SOD1. Moreover, SOD1 that has been cysteinylated and peroxide oxidized in vitro comprised a set of PTMs that bear a striking resemblance to the myriad of PTMs observed in SOD1 purified from human tissue.
Departments of Biochemistry and Chemistry and Rosenstiel Basic Medical Sciences Research Center, Brandeis University , Waltham, Massachusetts 02454, United States.
Jared R
JR
Auclair
Joshua L
JL
Johnson
Qian
Q
Liu
Joseph P
JP
Salisbury
Melissa S
MS
Rotunno
Gregory A
GA
Petsko
Dagmar
D
Ringe
Robert H
RH
Brown
Daryl A
DA
Bosco
Jeffrey N
JN
Agar
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013116:Spinal Cord / Q000201:enzymology; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003545:Cysteine; D010100:Oxygen