2008
DOI: 10.1074/jbc.m801522200
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Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis

Abstract: Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G… Show more

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Cited by 93 publications
(96 citation statements)
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“…Consistent with this, the crystal structures for apoWT and metal-deficient mutant SOD1s (e.g. H46R, G85R, D124V, and S134N) show a structured ␤-barrel core with disorder of loops IV and VII (3,22,54,77). The importance of zinc binding to order loops IV and VII has been suggested by molecular dynamics simulations (78) and isothermal titration calorimetry (63); furthermore, bound copper is insufficient to order the loops in the absence of zinc binding (79).…”
Section: Discussionsupporting
confidence: 54%
“…Consistent with this, the crystal structures for apoWT and metal-deficient mutant SOD1s (e.g. H46R, G85R, D124V, and S134N) show a structured ␤-barrel core with disorder of loops IV and VII (3,22,54,77). The importance of zinc binding to order loops IV and VII has been suggested by molecular dynamics simulations (78) and isothermal titration calorimetry (63); furthermore, bound copper is insufficient to order the loops in the absence of zinc binding (79).…”
Section: Discussionsupporting
confidence: 54%
“…Similar electron density breaks were also observed for the structure of the apo state of the H46R SOD1 mutant (21), the only, up to now published structure of a completely metal-free SOD1 mutant. On the contrary, the structures of ALS-related SOD1 mutants, in the fully metalated state are very similar to each other, and particularly well ordered throughout the sequence (20)(21)(22)(23)(24)(25).…”
Section: Resultsmentioning
confidence: 93%
“…We selected the mutants A4V, V7E, G37R, T54R, G85R, G93A, I113T and V148I, featuring various properties as summarized in Table 1. We also selected a mutation (G85R) that destabilizes the zinc-binding site 44 , and a SOD1 mutation not currently linked to fALS (I35T), but which is reported to promote SOD1 aggregation 34 . With the exception of G85R, all the selected mutations occur far from the metal binding sites.…”
Section: Resultsmentioning
confidence: 99%