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.
journal_name
Proc Natl Acad Sci U S Aauthors
Lindberg MJ,Byström R,Boknäs N,Andersen PM,Oliveberg Mdoi
10.1073/pnas.0501957102keywords:
subject
Has Abstractpub_date
2005-07-12 00:00:00pages
9754-9issue
28eissn
0027-8424issn
1091-6490pii
0501957102journal_volume
102pub_type
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