fALS-associated WTL mutations in SOD1 are scattered throughout the P-barrel of the protein, including P-strands, loops connecting the P-strands, and the dimeric interface. The specific activities and spectroscopic properties of this group of mutants are nearly indistinguishable from the wild-type . The thermal stabilities of the WTL mutants in their metal bound forms are decreased by 1-7°C relative to the wild-type protein . However, the metal-free forms of these mutants are substantially destabilized compared to metal-free wild-type
SOD1 . The least stable apo-mutant, A4V, causes the most severe form of SODl-associated fALS, and patients harboring this mutation have a mean survival period of little over one year . This hints at the likely importance of the metal-deficient forms of pathogenic SOD1 proteins to the disease state.
Three-dimensional structures of several metal bound versions of the WTL class of pathogenic SOD1 mutants are known and these structures do not differ considerably from that of the wild-type [29,77,119-121]. Structures of G37R and G93A demonstrate increased mobility in the electrostatic loop and P-plug regions, respectively [29,119]. The A4V and I113T mutations are located within a hydrophobic pocket at the dimer interface and because of the molecular twofold, exert their effects reciprocally in each subunit. Although structurally similar to wild-type, the A4V and I113T mutant proteins display a slight shift of the two monomers relative to each other, indicative of an alteration of interactions across the dimer interface . Although the structural data of metal bound WTL mutants do give some clues as to how they differ from the wild-type protein, it is not immediately obvious how they might exert toxicity through aggregation.
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