Exposure of β6/β7-Loop in Zn/Cu Superoxide Dismutase (SOD1) Is Coupled to Metal Loss and Is Transiently Reversible during Misfolding

Shamchal Bakavayev, Shirel Argueti, Nachiyappan Venkatachalam, Galit Yehezkel, Alexandra Stavsky, Zeev Barak, Adrian Israelson, Stanislav Engel

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Upon losing its structural integrity (misfolding), SOD1 acquires neurotoxic properties to become a pathogenic protein in ALS, a neurodegenerative disease targeting motor neurons; understanding the mechanism of misfolding may enable new treatment strategies for ALS. Here, we reported a monoclonal antibody, SE21, targeting the β6/β7-loop region of SOD1. The exposure of this region is coupled to metal loss and is entirely reversible during the early stages of misfolding. By using SE21 mAb, we demonstrated that, in apo-SOD1 incubated under the misfolding-promoting conditions, the reversible phase, during which SOD1 is capable of restoring its nativelike conformation in the presence of metals, is followed by an irreversible structural transition, autocatalytic in nature, which takes place prior to the onset of SOD1 aggregation and results in the formation of atypical apo-SOD1 that is unable to bind metals. The reversible phase defines a window of opportunity for pharmacological intervention using metal mimetics that stabilize SOD1 structure in its nativelike conformation to attenuate the spreading of the misfolding signal and disease progression by preventing the exposure of pathogenic SOD1 epitopes. Phenotypically similar apo-SOD1 species with impaired metal binding properties may also be produced via oxidation of Cys111, underscoring the diversity of SOD1 misfolding pathways.

Original languageEnglish
Pages (from-to)49-62
Number of pages14
JournalACS Chemical Neuroscience
Volume12
Issue number1
DOIs
StatePublished - 6 Jan 2021

Keywords

  • ALS
  • Amyotrophic lateral sclerosis
  • Lou Gehrig disease
  • SOD1
  • Zn/Cu superoxide dismutase
  • copper cofactor
  • fALS mutants
  • hydrogen peroxide
  • monoclonal antibody
  • oxidation
  • oxidative stress
  • protein misfolding
  • sulfenic acid
  • sulfinic acid
  • sulfonic acid
  • zinc cofactors

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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