Voltage-Induced Misfolding of Zinc-Replete ALS Mutant
Superoxide Dismutase‑1
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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