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Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity.

Neurobiology of disease | Feb 26, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17157513

The ubiquitin-proteasome system (UPS) is involved in the pathogenetic mechanisms of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Dorfin is a ubiquitin ligase (E3) that degrades mutant SOD1 proteins, which are responsible for familial ALS. Although Dorfin has potential as an anti-ALS molecule, its life in cells is short. To improve its stability and enhance its E3 activity, we developed chimeric proteins containing the substrate-binding hydrophobic portion of Dorfin and the U-box domain of the carboxyl terminus of Hsc70-interacting protein (CHIP), which has strong E3 activity through the U-box domain. All the Dorfin-CHIP chimeric proteins were more stable in cells than was wild-type Dorfin (Dorfin(WT)). One of the Dorfin-CHIP chimeric proteins, Dorfin-CHIP(L), ubiquitylated mutant SOD1 more effectively than did Dorfin(WT) and CHIP in vivo, and degraded mutant SOD1 protein more rapidly than Dorfin(WT) does. Furthermore, Dorfin-CHIP(L) rescued neuronal cells from mutant SOD1-associated toxicity and reduced the aggresome formation induced by mutant SOD1 more effectively than did Dorfin(WT).

Pubmed ID: 17157513 RIS Download

Mesh terms: Amyotrophic Lateral Sclerosis | Animals | Cell Death | Cell Line | DNA-Binding Proteins | Humans | Mice | Mutation | Nerve Degeneration | Neurotoxins | Proteasome Endopeptidase Complex | Recombinant Fusion Proteins | Superoxide Dismutase | Ubiquitin | Ubiquitin-Protein Ligases

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