Systematically Perturbed Folding Patterns of Amyotrophic Lateral Sclerosis (ALS)-Associated SOD1 Mutants

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-07, Vol.102 (28), p.9754-9759
• Main Authors: Lindberg, Mikael J., Byström, Roberth, Boknäs, Niklas, Andersen, Peter M., Oliveberg, Mikael, Fersht, Alan R.
• Format: Article
• Language: English
• Subjects: Aggregation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - classification; Amyotrophic Lateral Sclerosis - genetics; Biochemistry; Biological Sciences; Chromatography, Gel; Dimerization; Dimers; Disease Progression; Genetic mutation; Genetic Variation; Humans; Kinetics; Models, Molecular; Monomers; Mutation; Mutation, Missense - genetics; Nervous system diseases; neurodegenerative disease; Neurodegenerative diseases; Prognosis; Protein Folding; Protein refolding; Protein stability; Proteins; Superoxide Dismutase - genetics; Superoxide Dismutase-1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0501957102

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.