Aggregate formation in Cu,Zn superoxide dismutase-related proteins

Marjatta Son, C. Dyan Cloyd, Jeffrey D. Rothstein, Bhagya Rajendran, Jeffrey L. Elliott

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Aggregation of Cu,Zn superoxide dismutase (SOD1) protein is a pathologic hallmark of familial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene, although the structural motifs within mutant SOD1 that are responsible for its aggregation are unknown. Copper chaperone for SOD1 (CCS) and extracellular Cu,Zn superoxide dismutase (SOD3) have some sequence identity with SOD1, particularly in the regions of metal binding, but play no significant role in mutant SOD1-induced disease. We hypothesized that it would be possible to form CCS- or SOD3-positive aggregates by making these molecules resemble mutant SOD1 via the introduction of point mutations in codons homologous to a disease causing G85R SOD1 mutation. Using an in vitro assay system, we found that expression of wild type human CCS or a modified intracellular wild type SOD3 does not result in significant aggregate formation. In contrast, expression of G168R CCS or G146R SOD3 produced aggregates as evidenced by the presence of high molecular weight protein complexes on Western gels or inclusion bodies on immunofluorescence. CCS- and SOD3-positive inclusions appear to be ubiquitinated and localized to aggresomes. These results suggest that proteins sharing structural similarities to mutant SOD1 are also at risk for aggregate formation.

Original languageEnglish (US)
Pages (from-to)14331-14336
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number16
DOIs
StatePublished - Apr 18 2003

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Copper
Proteins
Agglomeration
Mutation
Inclusion Bodies
Point Mutation
Codon
Fluorescent Antibody Technique
Assays
Genes
Molecular Weight
Gels
Metals
Molecular weight
Superoxide Dismutase-1
Superoxide Dismutase
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

Aggregate formation in Cu,Zn superoxide dismutase-related proteins. / Son, Marjatta; Cloyd, C. Dyan; Rothstein, Jeffrey D.; Rajendran, Bhagya; Elliott, Jeffrey L.

In: Journal of Biological Chemistry, Vol. 278, No. 16, 18.04.2003, p. 14331-14336.

Research output: Contribution to journalArticle

Son, Marjatta ; Cloyd, C. Dyan ; Rothstein, Jeffrey D. ; Rajendran, Bhagya ; Elliott, Jeffrey L. / Aggregate formation in Cu,Zn superoxide dismutase-related proteins. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 16. pp. 14331-14336.
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