Amyotrophic lateral sclerosis-associated copper/zinc superoxide dismutase mutations preferentially reduce the repulsive charge of the proteins.
We provide bioinformatical evidence that protein charge plays a key role in the disease mechanism of amyotrophic lateral sclerosis (ALS). Analysis of 100 ALS-associated mutations in copper/zinc superoxide dismutase (SOD1) shows that these are site-selective with a preference to decrease the proteins' net repulsive charge. For each SOD1 monomer this charge is normally -6. Because biomolecules as a rule maintain net negative charge to assure solubility in the cellular interior, the result lends support to the hypothesis of protein aggregation as an initiating event in the ALS pathogenesis. The strength of the preferential reduction of repulsive charge is higher in SOD1-associated ALS than in other inherited protein disorders.
Sandelin
Erik
E
Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
Nordlund
Anna
A
Andersen
Peter M
PM
Marklund
Stefan S L
SS
Oliveberg
Mikael
M
D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D003062:Codon; D019295:Computational Biology; D004252:DNA Mutational Analysis; D015894:Genome, Human; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D012995:Solubility; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics*
D003062:Codon; D013482:Superoxide Dismutase