FALS mutations in Cu, Zn superoxide dismutase destabilize the dimer and increase dimer dissociation propensity: A large-scale thermodynamic analysis

• Published in: Amyloid Vol. 13; no. 4; pp. 226 - 235
• Main Authors: Khare, Sagar D., Caplow, Michael, Dokholyan, Nikolay V.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01-12-2006; Taylor & Francis; Taylor & Francis Ltd
• Subjects: aggregation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; dimer dissociation; Dimerization; Enzyme Stability; Humans; Models, Molecular; molecular dynamics simulations; Mutation; stability; Superoxide Dismutase - chemistry; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Thermodynamics; Zn superoxide dismutase
• ISSN: 1350-6129; 1744-2818
• DOI: 10.1080/13506120600960486

Mutations in the dimeric enzyme Cu, Zn superoxide dismutase (SOD1) leading to its aggregation are implicated in the toxicity in familial amyotrophic lateral sclerosis (FALS). We and others have previously shown that aggregation occurs by a pathway involving dimer dissociation, metal-loss from monomers and multimeric assembly of apo-SOD1 monomers. We postulate that FALS mutations cause enhanced aggregation by affecting one or more steps in the pathway, and computationally test this postulate for 75 known mis-sense FALS mutants of SOD1. Based on an extensive thermodynamic analysis of the stability of apo-dimer and apo-monomer forms of these mutants, we classify the mutations into the following groups: 70 out of 75 mutations in SOD1 lead to (i) decreased dimer stability, and or (ii) increased dimer dissociation, compared to wild type, and four mutations lead to (iii) decreased monomer stability compared to wild type. Our results suggest that enhanced aggregation of SOD1 in FALS occurs due to an increased population of mutant SOD1 apo-monomers compared to wild type. The dissociation of multimeric proteins induced by diverse mutations may be a common theme in several human diseases.