Calcium binding to gatekeeper residues flanking aggregation-prone segments underlies non-fibrillar amyloid traits in superoxide dismutase 1 (SOD1)

Sílvia G. Estácio, Sonia Cristina Solano, Joana S. Cristóvão, Patrícia F N Faísca, Claudio Emanuel Gomes

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Calcium deregulation is a central feature among neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Calcium accumulates in the spinal and brain stem motor neurons of ALS patients triggering multiple pathophysiological processes which have been recently shown to include direct effects on the aggregation cascade of superoxide dismutase 1 (SOD1). SOD1 is a Cu/Zn enzyme whose demetallated form is implicated in ALS protein deposits, contributing to toxic gain of function phenotypes. Here we undertake a combined experimental and computational study aimed at establishing the molecular details underlying the regulatory effects of Ca2 + over SOD1 aggregation potential. Isothermal titration calorimetry indicates entropy driven low affinity association of Ca2 + ions to apo SOD1, at pH 7.5 and 37°C. Molecular dynamics simulations denote a noticeable loss of native structure upon Ca2 + association that is especially prominent at the zinc-binding and electrostatic loops, whose decoupling is known to expose the central SOD1 β-barrel triggering aggregation. Structural mapping of the preferential apo SOD1 Ca2 + binding locations reveals that among the most frequent ligands for Ca2 + are negatively-charged gatekeeper residues located in boundary positions with respect to segments highly prone to edge-to-edge aggregation. Calcium interactions thus diminish gatekeeping roles of these residues, by shielding repulsive interactions via stacking between aggregating β-sheets, partly blocking fibril formation and promoting amyloidogenic oligomers such as those found in ALS inclusions. Interestingly, many fALS mutations occur at these positions, disclosing how Ca2 + interactions recreate effects similar to those of genetic defects, a finding with relevance to understand sporadic ALS pathomechanisms.

Original languageEnglish
Pages (from-to)118-126
Number of pages9
JournalBiochimica Et Biophysica Acta-Proteins And Proteomics
Volume1854
Issue number2
DOIs
Publication statusPublished - 2015

Keywords

  • Electrostatic interaction
  • Gatekeeping residue
  • Isothermal titration calorimetry
  • Molecular dynamics
  • Protein aggregation
  • Protein dynamics

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