The Structure of Holo and Metal-deficient Wild-type Human Cu, Zn Superoxide Dismutase and its Relevance to Familial Amyotrophic Lateral Sclerosis

• Published in: Journal of molecular biology Vol. 328; no. 4; pp. 877 - 891
• Main Authors: Strange, Richard W., Antonyuk, Svetlana, Hough, Michael A., Doucette, Peter A., Rodriguez, Jorge A., Hart, P.John, Hayward, Lawrence J., Valentine, Joan S., Hasnain, S.Samar
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 09-05-2003
• Subjects: ALS, amyloid; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Binding Sites; Crystallography, X-Ray; Cu, Zn superoxide dismutase; Dimerization; familial amyotrophic lateral sclerosis; Humans; Metals - chemistry; Models, Chemical; Models, Molecular; Protein Conformation; Protein Structure, Secondary; SOD1; Superoxide Dismutase - chemistry; Zinc - chemistry; SALS, sporadic ALS; familial amyotrophic lateral sclerosis; SOD1, human cytosolic Cu,Zn superoxide dismutase; Cu, Zn superoxide dismutase; wtSOD1, wild-type SOD1; FALS, familial ALS; ALS, amyloid; SOD1; ALS, amyotrophic lateral sclerosis
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/S0022-2836(03)00355-3

Cu, Zn superoxide dismutase (SOD1) forms a crucial component of the cellular defence against oxidative stress. Zn-deficient wild-type and mutant human SOD1 have been implicated in the disease familial amyotrophic lateral sclerosis (FALS). We present here the crystal structures of holo and metal-deficient (apo) wild-type protein at 1.8
Å resolution. The P21 wild-type holo enzyme structure has nine independently refined dimers and these combine to form a “trimer of dimers” packing motif in each asymmetric unit. There is no significant asymmetry between the monomers in these dimers, in contrast to the subunit structures of the FALS G37R mutant of human SOD1 and in bovine Cu,Zn SOD. Metal-deficient apo SOD1 crystallizes with two dimers in the asymmetric unit and shows changes in the metal-binding sites and disorder in the Zn binding and electrostatic loops of one dimer, which is devoid of metals. The second dimer lacks Cu but has ∼20% occupancy of the Zn site and remains structurally similar to wild-type SOD1. The apo protein forms a continuous, extended arrangement of β-barrels stacked up along the short crystallographic
b-axis, while perpendicular to this axis, the constituent β-strands form a zig-zag array of filaments, the overall arrangement of which has a similarity to the common structure associated with amyloid-like fibrils.