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Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9754-9. Epub 2005 Jun 29.

Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants.

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1
Departments of Biochemistry and Clinical Neuroscience, Umeå University, S-901 87 Umeå, Sweden.

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative syndrome associated with 114 mutations in the gene encoding the cytosolic homodimeric enzyme Cu/Zn superoxide dismutase (SOD). In this article, we report that amyotrophic lateral sclerosis-associated SOD mutations with distinctly different disease progression can be rationalized in terms of their folding patterns. The mutations are found to perturb the protein in multiple ways; they destabilize the precursor monomers (class 1), weaken the dimer interface (class 2), or both at the same time (class 1 + 2). A shared feature of the mutational perturbations is a shift of the folding equilibrium toward poorly structured SOD monomers. We observed a link, coupled to the altered folding patterns, between protein stability, net charge, and survival time for the patients carrying the mutations.

PMID:
15987780
PMCID:
PMC1174986
DOI:
10.1073/pnas.0501957102
[Indexed for MEDLINE]
Free PMC Article
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