Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2004 Apr 20;101(16):5976-81.
doi: 10.1073/pnas.0305143101. Epub 2004 Mar 31.

Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants

Michael A Hough  1 , J Günter Grossmann, Svetlana V Antonyuk, Richard W Strange, Peter A Doucette, Jorge A Rodriguez, Lisa J Whitson, P John Hart, Lawrence J Hayward, Joan Selverstone Valentine, S Samar Hasnain
Affiliations

Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants

Michael A Hough et al. Proc Natl Acad Sci U S A. .

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.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Images of 2Fobs – Fcalc electron density maps, contoured at 1.5 σ are shown for wtSOD (a): the Ala-4 side-chain Cβ forms a 3.6-Å hydrophobic contact to the Cδ2 atom of Ile-113. (b) A4V: The mutation is clearly defined in the electron density. Hydrophobic close contacts are indicated by dashed lines. Steric constraints due to the bulkier Val side chain in the mutant structure cause a shift in the position of Ile-113 due to the replacement of the single 3.6-Å Ala-4Cβ–Ile-113Cδ2 hydrophobic interaction with two others, namely from Val-4Cγ1 to Ile-113Cγ1 (3.8 Å) and Ile-113Cδ2 (3.9 Å). In addition, a contact is formed between Val-4Cγ2 and Ile-149Cγ2 (3.5 Å). (c) I113T: The close contact between Ala-4Cβ and Ile-113C δ2 is lost.
Fig. 2.
Fig. 2.
Shift in the relative orientation of the two subunits of SOD on mutation of Ala-4 to Val. Dimers of A4V (red) and the wild-type structure (blue) were superimposed by least-squares superposition of the interface residues (114, 51–53, and 149–153). The relative position of the two monomers is significantly altered in A4V. This shift takes the form of a small rotation and a larger corkscrew-like motion about the normal to the twofold pseudo symmetry axis defined between the two molecules. The six molecules of A4V express this shift to different levels. In general, molecules with higher thermal parameters (and hence higher mobility) show the larger shifts. The maximum shift is shown by dimer 5 in A4V (I and J) and this shift is shown in the figure.
Fig. 3.
Fig. 3.
Solution x-ray scattering profiles of A4V and I113T mutants and human wtSOD, measured at 4°C (a), as well as native BSOD recorded at different temperatures (b). The profiles result from merging the low- and high-concentration data in the small- and wide-angle region.
Fig. 4.
Fig. 4.
Two perpendicular views of the shapes reconstructed from the wild-type, A4V, and I113T scattering profiles shown in Fig. 3a. Each shape reconstruction is performed with a dimer obeying twofold symmetry in which each subunit is represented by closely packed spheres. The wild-type crystal structure (PDB ID code 1HL5) has been superimposed in the scattering envelope of wtSOD1.
See this image and copyright information in PMC

Comment in

  • A possible therapeutic target for Lou Gehrig's disease.
    Ray SS, Lansbury PT Jr. Ray SS, et al. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5701-2. doi: 10.1073/pnas.0401934101. Epub 2004 Apr 12. Proc Natl Acad Sci U S A. 2004. PMID: 15079068 Free PMC article. No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Brown, R. H., Jr. (1995) Cell 80, 687–692. - PubMed
    1. Maier, C. M. & Chan, P. K. (2002) Neuroscientist 8, 323–334. - PubMed
    1. Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O'Regan, J. P., Deng, H. X., et al. (1993) Nature 362, 59–56. - PubMed
    1. Gaudette, M., Hirano, M. & Siddique, T. (2000) Amyotroph. Lateral Scler. 1, 83–89. - PubMed
    1. Cleveland, D. W. & Rothstein, J. D. (2001) Nat. Rev. Neurosci. 11, 806–819. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources