title: Proteasomal degradation of mutant superoxide dismutases linked to amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Laboratory of Biochemistry, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0812, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Noto
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Whitson
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Cao
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Levine
mesh_terms: 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
chemical_list: 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