Cu,Zn superoxide dismutase maturation and activity are regulated by COMMD1.
The maturation and activation of the anti-oxidant Cu,Zn superoxide dismutase (SOD1) are highly regulated processes that require several post-translational modifications. The maturation of SOD1 is initiated by incorporation of zinc and copper ions followed by disulfide oxidation leading to the formation of enzymatically active homodimers. Our present data indicate that homodimer formation is a regulated final step in SOD1 maturation and implicate the recently characterized copper homeostasis protein COMMD1 in this process. COMMD1 interacts with SOD1, and this interaction requires CCS-mediated copper incorporation into SOD1. COMMD1 does not regulate disulfide oxidation of SOD1 but reduces the level of SOD1 homodimers. RNAi-mediated knockdown of COMMD1 expression results in a significant induction of SOD1 activity and a consequent decrease in superoxide anion concentrations, whereas overexpression of COMMD1 exerts exactly the opposite effects. Here, we identify COMMD1 as a novel protein regulating SOD1 activation and associate COMMD1 function with the production of free radicals.
Vonk
Willianne I M
WI
Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, The Netherlands. w.i.m.vonk@umcutrecht.nl
Wijmenga
Cisca
C
Berger
Ruud
R
van de Sluis
Bart
B
Klomp
Leo W J
LW
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; D002352:Carrier Proteins; C103799:Commd1 protein, mouse; D011506:Proteins; C000606290:SOD1 protein, human; D013481:Superoxides; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1