Wildtypelike fAls Mutants

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 [47]. The thermal stabilities of the WTL mutants in their metal bound forms are decreased by 1-7°C relative to the wild-type protein [116]. However, the metal-free forms of these mutants are substantially destabilized compared to metal-free wild-type

SOD1 [117]. 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 [118]. 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 [121]. 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.

Was this article helpful?

0 0
Detoxify the Body

Detoxify the Body

Need to Detoxify? Discover The Secrets to Detox Your Body The Quick & Easy Way at Home! Too much partying got you feeling bad about yourself? Or perhaps you want to lose weight and have tried everything under the sun?

Get My Free Ebook


Post a comment