3QQD

Human SOD1 H80R variant, P212121 crystal form

Replaces:  3H2R

Summary for 3QQD

• Entry DOI: 10.2210/pdb3qqd/pdb
• Related: 3H2P 3H2Q
• Descriptor: Superoxide dismutase [Cu-Zn], ZINC ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: oxidoreductase, human cu, zn superoxide dismutase, antioxidant, metal-binding, amyotrophic lateral sclerosis, disease mutation, disulfide bond
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P00441 P00441
• Total number of polymer chains: 2
• Total formula weight: 32132.24

Authors

Seetharaman, S.V.,Winkler, D.D.,Taylor, A.B.,Cao, X.,Whitson, L.J.,Doucette, P.A.,Valentine, J.S.,Schirf, V.,Demeler, B.,Carroll, M.C.,Culotta, V.C.,Hart, P.J. (deposition date: 2011-02-15, release date: 2011-03-09, Last modification date: 2023-12-06)

Primary citation

Seetharaman, S.V.,Winkler, D.D.,Taylor, A.B.,Cao, X.,Whitson, L.J.,Doucette, P.A.,Valentine, J.S.,Schirf, V.,Demeler, B.,Carroll, M.C.,Culotta, V.C.,Hart, P.J.
Disrupted zinc-binding sites in structures of pathogenic SOD1 variants D124V and H80R.
Biochemistry, 49:5714-5725, 2010

PubMed Abstract: Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we present structures of the pathogenic SOD1 variants D124V and H80R, both of which demonstrate compromised zinc-binding sites. The disruption of the zinc-binding sites in H80R SOD1 leads to conformational changes in loop elements, permitting non-native SOD1-SOD1 interactions that mediate the assembly of these proteins into higher-order filamentous arrays. Analytical ultracentrifugation sedimentation velocity experiments indicate that these SOD1 variants are more prone to monomerization than the wild-type enzyme. Although D124V and H80R SOD1 proteins appear to have fully functional copper-binding sites, inductively coupled plasma mass spectrometery (ICP-MS) and anomalous scattering X-ray diffraction analyses reveal that zinc (not copper) occupies the copper-binding sites in these variants. The absence of copper in these proteins, together with the results of covalent thiol modification experiments in yeast strains with and without the gene encoding the copper chaperone for SOD1 (CCS), suggests that CCS may not fully act on newly translated forms of these polypeptides. Overall, these findings lend support to the hypothesis that immature mutant SOD1 species contribute to toxicity in SOD1-linked ALS.

PubMed: 20515040
DOI: 10.1021/bi100314n

Experimental method

X-RAY DIFFRACTION (1.653 Å)