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SOD1 Mutations Targeting Surface Hydrogen Bonds Promote Amyotrophic Lateral Sclerosis without Reducing Apo-state Stability
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
2010 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, nr 25, s. 19544-19552Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apoSOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS- provoking mutations. As an alternative test of the structure- disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS- provoking mutations whose only effect on apoSOD1 is the elimination or introduction of a single charge, i.e. D76V/Y, D101N, and N139D/K. The thermodynamic stability and folding behavior of these mutants are indistinguishable from the wild-type control. Moreover, D101N is an outlier in the plot of stability loss versus patient survival time by having rapid disease progression. Commonto the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS- associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS- provoking features.

Ort, förlag, år, upplaga, sidor
2010. Vol. 285, nr 25, s. 19544-19552
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Naturvetenskap
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URN: urn:nbn:se:su:diva-50656DOI: 10.1074/jbc.M109.086074ISI: 000278727800064OAI: oai:DiVA.org:su-50656DiVA, id: diva2:383205
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authorCount :4Tillgänglig från: 2011-01-04 Skapad: 2010-12-30 Senast uppdaterad: 2017-12-11Bibliografiskt granskad

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Oliveberg, Mikael
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Institutionen för biokemi och biofysik
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Journal of Biological Chemistry
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