Peptide Bond Cleavage by Ni(II) Ions within the Nuclear Localization Signal Sequence

Chem Biodivers. 2020 Feb;17(2):e1900652. doi: 10.1002/cbdv.201900652. Epub 2020 Jan 28.


Nickel is harmful to humans, being both carcinogenic and allergenic. However, the mechanisms of this toxicity are still unresolved. We propose that Ni(II) ions disintegrate proteins by hydrolysis of peptide bonds preceding the Ser/Thr-Xaa-His sequences. Such sequences occur in nuclear localization signals (NLSs) of human phospholipid scramblase 1, Sam68-like mammalian protein 2, and CLK3 kinase. We performed spectroscopic experiments showing that model nonapeptides derived from these NLSs bind Ni(II) at physiological pH. We also proved that these sequences are prone to Ni(II) hydrolysis. Thus, the aforementioned NLSs may be targets for nickel toxicity. This implies that Ni(II) ions disrupt the transport of some proteins from cytoplasm to cell nucleus.

Keywords: allergy; cancer; hydrolysis; nickel; peptides.

MeSH terms

  • Amino Acid Sequence
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Ions / chemistry
  • Kinetics
  • Nickel / chemistry*
  • Nickel / metabolism
  • Nickel / toxicity
  • Peptides / chemistry*
  • Peptides / metabolism
  • Phospholipid Transfer Proteins / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Sequence Alignment
  • Spectrophotometry


  • Ions
  • PLSCR1 protein, human
  • Peptides
  • Phospholipid Transfer Proteins
  • Nickel
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases