A mechanism for propagated SOD1 misfolding from frustration analysis of a G85R mutant protein assembly

• Published in: Biochemical and biophysical research communications 2016-09, Vol.478 (4), p.1634-1639
• Main Author: Healy, Eamonn F.
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; crystal structure; Crystallography, X-Ray; Dehydrons; Electrostatic loop; Frustration contacts; G85R SOD1 mutant; Humans; Hydrogen Bonding; landscapes; Molecular Dynamics Simulation; Mutant Proteins - chemistry; Mutant Proteins - metabolism; mutants; Mutation, Missense; Prions - chemistry; Protein Conformation; Protein Folding; Protein Multimerization; Protein Subunits - chemistry; Protein Subunits - genetics; Protein Subunits - metabolism; Static Electricity; Superoxide dismutase; Superoxide Dismutase-1 - chemistry; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.08.172

Application of landscape theory and the dehydron hypothesis to a crystal structure of a G85R mutant superoxide dismutase (SOD1) tetrameric complex allows for the description of a prion-like hypothesis that serves to explain propagated SOD1 misfolding. We have developed two conformational-change scenarios, one local to the ESL at the complex interface, and a second displacement at the ESL of the otherdimeric subunit. When taken together these provide for a prion-like mechanism that can serve to explain the observed conversion of wtSOD1 to a misfolded form by the G85R mutant. [Display omitted] •Frustration analysis of the G85R superoxide dismutase (SOD1) mutant crystal structure.•A proposed mechanism for prion-like propagation of SOD1 misfolding.•A local mechanism based on induced conformational change at the electrostatic loop.•A local mechanism based on the disruption of correlated motion between SOD1 subunits.