Aggregation modulating elements in mutant human superoxide dismutase 1.
Mutations in superoxide dismutase 1 (SOD1) cause some forms of familial amyotrophic lateral sclerosis (fALS). Affected tissues of patients and transgenic mouse models of the disease accumulate misfolded and aggregated forms of the mutant protein. In the present study we have identified specific sequences in human SOD1 that modulate the aggregation of fALS mutant proteins. From our study of a panel of mutant proteins, we identify two sequence elements in human SOD1 (residues 42-50 and 109-123) that are critical in modulating the aggregation of the protein. These sequences are components of the 4th and 7th β-strands of the protein, and in the native structure are normally juxtaposed as elements of the core β-barrel. Our data suggest that some type of intermolecular interaction between these elements may occur in promoting mutant SOD1 aggregation.
Karch
Celeste M
CM
Department of Neuroscience, University of Florida, McKnight Brain Institute, Gainesville, 32610, USA. karchc@psychiatry.wustl.edu
Borchelt
David R
DR
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D051379:Mice; D009154:Mutation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014162:Transfection
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1