Dimer Destabilization in Superoxide Dismutase May Result in Disease-Causing Properties: Structures of Motor Neuron Disease Mutants

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 destabiliza...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 16; pp. 5976 - 5981
Main Authors Hough, Michael A., Grossmann, J. Günter, Antonyuk, Svetlana V., Strange, Richard W., Doucette, Peter A., Rodriguez, Jorge A., Whitson, Lisa J., Hart, P. John, Hayward, Lawrence J., Valentine, Joan Selverstone, Hasnain, S. Samar, Petsko, Gregory A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 20.04.2004
National Acad Sciences
SeriesFrom the Cover
Subjects
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - enzymology
Amyotrophic Lateral Sclerosis - genetics
Atoms
Biological Sciences
Crystal structure
Crystallography, X-Ray
Dimerization
Dimers
Enzymes
Molecules
Monomers
Motor neuron disease
Mutation
Scattering, Radiation
Superoxide Dismutase - chemistry
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Superoxides
Ungulates
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Summary: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 Ile 113Thr (I113T) mutants to 1.9 and 1.6 Å, 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°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.
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To whom correspondence should be addressed at: CCLRC Daresbury Laboratory, Keckwick Lane, Warrington WA4 4AD, United Kingdom. E-mail: s.hasnain@dl.ac.uk.
Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved January 26, 2004
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 1UXM (A4V) and 1UXL (I113T)].
Abbreviations: ALS, amyotrophic lateral sclerosis; FALS, familial ALS; SALS, sporadic ALS; SOD, superoxide dismutase; wtSOD, wild-type SOD; BSOD, bovine SOD; A4V, the Ala4Val mutant of SOD1; I113T, the Ile113Thr mutant of SOD1.
See Commentary on page 5701.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0305143101