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SOD1 mutations targeting surface hydrogen bonds promote ALS without reducing apo-state stability
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Stockholms universitet.
2010 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 25, 19544-52 p.Article in journal (Refereed) 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 apo-SOD1 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 apo SOD1 is the elimination or introduction of a single charge, i.e., D76V/Y, D101N and N139D/K. The thermodynamic stability and folding behaviour of these mutants are indistinguishable from the wildtype control. Moreover, D101N is an outlier in the plot of stability loss vs. patient survival time by having rapid disease progression. Common to 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.

Place, publisher, year, edition, pages
The American Society for Biochemistry and Molecular Biology , 2010. Vol. 285, no 25, 19544-52 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-32503DOI: 10.1074/jbc.M109.086074ISI: 000278727800064PubMedID: 20189984OAI: diva2:303743
Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2011-04-07Bibliographically approved

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Byström, RoberthAndersen, Peter MGröbner, Gerhard
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