Increased affinity for copper mediated by cysteine 111 in forms of mutant superoxide dismutase 1 linked to amyotrophic lateral sclerosis.
Mutations in Cu,Zn-superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (ALS). It has been proposed that neuronal cell death might occur due to inappropriately increased Cu interaction with mutant SOD1. Using Cu immobilized metal-affinity chromatography (IMAC), we showed that mutant SOD1 (A4V, G85R, and G93A) expressed in transfected COS7 cells, transgenic mouse spinal cord tissue, and transformed yeast possessed higher affinity for Cu than wild-type SOD1. Serine substitution for cysteine at the Cys111 residue in mutant SOD1 abolished the Cu interaction on IMAC. C111S substitution reversed the accelerated degradation of mutant SOD1 in transfected cells, suggesting that the Cys111 residue is critical for the stability of mutant SOD1. Aberrant Cu binding at the Cys111 residue may be a significant factor in altering mutant SOD1 behavior and may explain the benefit of controlling Cu access to mutant SOD1 in models of familial ALS.
Watanabe
Shohei
S
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Nagano
Seiichi
S
Duce
James
J
Kiaei
Mahmoud
M
Li
Qiao-Xin
QX
Tucker
Stephanie M
SM
Tiwari
Ashutosh
A
Brown
Robert H
RH
Beal
M Flint
MF
Hayward
Lawrence J
LJ
Culotta
Valeria C
VC
Yoshihara
Satoshi
S
Sakoda
Saburo
S
Bush
Ashley I
AI
D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002846:Chromatography, Affinity / Q000379:methods; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry* / Q000235:genetics; D004795:Enzyme Stability / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012694:Serine / Q000737:chemistry / Q000235:genetics; D013116:Spinal Cord / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014162:Transfection
C000606290:SOD1 protein, human; D012694:Serine; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003545:Cysteine