Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants.
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.
Departments of Biochemistry and Clinical Neuroscience, Umeå University, S-901 87 Umeå, Sweden.
Mikael J
MJ
Lindberg
Roberth
R
Byström
Niklas
N
Boknäs
Peter M
PM
Andersen
Mikael
M
Oliveberg
D000690:Amyotrophic Lateral Sclerosis / Q000145:classification / Q000235:genetics*; D002850:Chromatography, Gel; D019281:Dimerization; D018450:Disease Progression; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D011379:Prognosis; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1