UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

4-9-2010

Document Type

Article

Subjects

Amyotrophic Lateral Sclerosis; Binding Sites; Humans; Kinetics; Metals; *Mutation, Missense; Protein Folding; Protein Multimerization; Superoxide Dismutase; Thermodynamics

Disciplines

Life Sciences | Medicine and Health Sciences | Women's Studies

Abstract

Amino acid replacements at dozens of positions in the dimeric protein human, Cu,Zn superoxide dismutase (SOD1) can cause amyotrophic lateral sclerosis (ALS). Although it has long been hypothesized that these mutations might enhance the populations of marginally-stable aggregation-prone species responsible for cellular toxicity, there has been little quantitative evidence to support this notion. Perturbations of the folding free energy landscapes of metal-free versions of five ALS-inducing variants, A4V, L38V, G93A, L106V and S134N SOD1, were determined with a global analysis of kinetic and thermodynamic folding data for dimeric and stable monomeric versions of these variants. Utilizing this global analysis approach, the perturbations on the global stability in response to mutation can be partitioned between the monomer folding and association steps, and the effects of mutation on the populations of the folded and unfolded monomeric states can be determined. The 2- to 10-fold increase in the population of the folded monomeric state for A4V, L38V and L106V and the 80- to 480-fold increase in the population of the unfolded monomeric states for all but S134N would dramatically increase their propensity for aggregation through high-order nucleation reactions. The wild-type-like populations of these states for the metal-binding region S134N variant suggest that even wild-type SOD1 may also be prone to aggregation in the absence of metals.

Rights and Permissions

Citation: PLoS One. 2010 Apr 9;5(4):e10064. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

20404910

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