title: Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants.
abstract: More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile113Thr (I113T) mutants to 1.9 and 1.6 A, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80 degrees C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.
authors.affiliation: Molecular Biophysics Group, Council for the Central Laboratory of the Research Councils, Daresbury Laboratory, Warrington, Cheshire WA4 4AD, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hough
authors.forename: J Günter
authors.initials: JG
authors.lastname: Grossmann
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Antonyuk
authors.forename: Richard W
authors.initials: RW
authors.lastname: Strange
authors.forename: Peter A
authors.initials: PA
authors.lastname: Doucette
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Rodriguez
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Whitson
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Hayward
authors.forename: Joan Selverstone
authors.initials: JS
authors.lastname: Valentine
authors.forename: S Samar
authors.initials: SS
authors.lastname: Hasnain
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D018360:Crystallography, X-Ray; D019281:Dimerization; D009154:Mutation; D012542:Scattering, Radiation; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D013482:Superoxide Dismutase