Sökning: WFRF:(Andersen Peter M.)
> (2010-2014) >
SOD1 mutations targ...
SOD1 mutations targeting surface hydrogen bonds promote ALS without reducing apo-state stability
-
- Byström, Roberth (författare)
- Umeå universitet,Kemiska institutionen
-
- Andersen, Peter M (författare)
- Umeå universitet,Neurologi
-
- Gröbner, Gerhard (författare)
- Umeå universitet,Kemiska institutionen
-
visa fler...
-
- Oliveberg, Mikael (författare)
- Stockholms universitet
-
visa färre...
-
(creator_code:org_t)
- The American Society for Biochemistry and Molecular Biology, 2010
- 2010
- Engelska.
-
Ingår i: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 285:25, s. 19544-52
- Relaterad länk:
-
https://urn.kb.se/re...
-
visa fler...
-
https://doi.org/10.1...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- MEDICINE
- MEDICIN
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas