Proteasomal degradation of mutant superoxide dismutases linked to amyotrophic lateral sclerosis.
Mutations in copper-zinc superoxide dismutase cause the neurodegenerative disease amyotrophic lateral sclerosis. Many of the mutant proteins have increased turnover in vivo and decreased thermal stability. Here we show that purified, metal-free superoxide dismutases are degraded in vitro by purified 20 S proteasome in the absence of ATP and without ubiquitinylation, whereas their metal-bound counterparts are not. The rate of degradation by the proteasome varied among the mutants studied, and the rate correlated with the in vivo half-life. The monomeric forms of both mutant and wild-type superoxide dismutase are particularly susceptible to degradation by the proteasome. Exposure of hydrophobic regions as a consequence of decreased thermal stability may allow the proteasome to recognize these molecules as non-native.
Di Noto
Luca
L
Laboratory of Biochemistry, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0812, USA.
Whitson
Lisa J
LJ
Cao
Xiaohang
X
Hart
P John
PJ
Levine
Rodney L
RL
D000255:Adenosine Triphosphate / Q000737:chemistry; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004220:Disulfides / Q000737:chemistry; D006358:Hot Temperature; D008670:Metals / Q000737:chemistry; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics* / Q000502:physiology; D000072105:Superoxide Dismutase-1; D013696:Temperature; D013997:Time Factors; D025801:Ubiquitin / Q000737:chemistry
D004220:Disulfides; D008670:Metals; D010455:Peptides; D025801:Ubiquitin; D000255:Adenosine Triphosphate; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D046988:Proteasome Endopeptidase Complex