title: Wild-type Cu/Zn superoxide dismutase stabilizes mutant variants by heterodimerization.
abstract: Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) are responsible for a subset of amyotrophic lateral sclerosis cases presumably by the acquisition of as yet unknown toxic properties. Additional overexpression of wild-type SOD1 in mutant SOD1 transgenic mice did not improve but rather accelerated the disease course. Recently, it was documented that the presence of wild-type SOD1 (SOD(WT)) reduced the aggregation propensity of mutant SOD1 by the formation of heterodimers between mutant and SOD1(WT) and that these heterodimers displayed at least a similar toxicity in cellular and animal models. In this study we investigated the biochemical and biophysical properties of obligate SOD1 dimers that were connected by a peptide linker. Circular dichroism spectra indicate an increased number of unstructured residues in SOD1 mutants. However, SOD1(WT) stabilized the folding of heterodimers compared to mutant homodimers as evidenced by an increase in resistance against proteolytic degradation. Heterodimerization also reduced the affinity of mutant SOD1 to antibodies detecting misfolded SOD1. In addition, the formation of obligate dimers resulted in a detection of substantial dismutase activity even of the relatively labile SOD1(G85R) mutant. These data indicate that soluble, dismutase-active SOD1 dimers might contribute at least partially to mutant SOD1 toxicity.
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Weichert
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Besemer
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Liebl
authors.affiliation: Institute of Molecular Biophysics of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Hellmann
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Koziollek-Drechsler
authors.affiliation: Department of Medical Biophysics, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada; Ontario Cancer Institute, 101 College St., Toronto, ON M5G 1L7, Canada; MaRS Centre, 101 College St., Toronto, ON M5G 1L7, Canada.
authors.forename: Philbert
authors.initials: P
authors.lastname: Ip
authors.affiliation: Institute of Molecular Biophysics of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Decker
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 3H2, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3H2, Canada.
authors.forename: Janice
authors.initials: J
authors.lastname: Robertson
authors.affiliation: Department of Medical Biophysics, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
authors.forename: Avijit
authors.initials: A
authors.lastname: Chakrabartty
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, Germany. Electronic address: clement@uni-mainz.de.
authors.forename: Albrecht M
authors.initials: AM
authors.lastname: Clement
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D055503:Protein Multimerization; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Dismutase activity; Heterodimerization; Misfolding; Mutant homodimers; Protein aggregation; SEDI; SOD1; USOD