title: Voltage-Induced Misfolding of Zinc-Replete ALS Mutant Superoxide Dismutase-1.
abstract: The monomerization of Cu, Zn superoxide dismutase (SOD1) is an early step along pathways of misfolding linked to amyotrophic lateral sclerosis (ALS). Monomerization requires the reversal of two post-translational modifications that are thermodynamically favorable: (i) dissociation of active-site metal ions and (ii) reduction of intramolecular disulfide bonds. This study found, using amide hydrogen/deuterium (H/D) exchange, capillary electrophoresis, and lysine-acetyl protein charge ladders, that ALS-linked A4V SOD1 rapidly monomerizes and partially unfolds in an external electric field (of physiological strength), without loss of metal ions, exposure to disulfide-reducing agents, or Joule heating. Voltage-induced monomerization was not observed for metal-free A4V SOD1, metal-free WT SOD1, or metal-loaded WT SOD1. Computational modeling suggested a mechanism for this counterintuitive effect: subunit macrodipoles of dimeric SOD1 are antiparallel and amplified 2-fold by metal coordination, which increases torque at the dimer interface as subunits rotate to align with the electric field.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Acerson
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Shuford
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Shaw
mesh_terms: D002152:Calorimetry, Differential Scanning; D041961:Deuterium Exchange Measurement; D019075:Electrophoresis, Capillary; D006801:Humans; D008956:Models, Chemical; D009154:Mutation / Q000235:genetics; D017510:Protein Folding / Q000528:radiation effects; D011499:Protein Processing, Post-Translational; D055672:Static Electricity; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc
keywords: Aggregation; SOD1; amyotrophic lateral sclerosis; electric field; voltage; zinc