Human annexins A1, A2, and A8 as potential molecular targets for Ni(II) ions

Chem Res Toxicol. 2014 Nov 17;27(11):1996-2009. doi: 10.1021/tx500337w. Epub 2014 Oct 20.


Nickel is harmful for humans, but molecular mechanisms of its toxicity are far from being fully elucidated. One of such mechanisms may be associated with the Ni(II)-dependent peptide bond hydrolysis, which occurs before Ser/Thr in Ser/Thr-Xaa-His sequences. Human annexins A1, A2, and A8, proteins modulating the immune system, contain several such sequences. To test if these proteins are potential molecular targets for nickel toxicity we characterized the binding of Ni(II) ions and hydrolysis of peptides Ac-KALTGHLEE-am (A1-1), Ac-TKYSKHDMN-am (A1-2), and Ac-GVGTRHKAL-am (A1-3), from annexin A1, Ac-KMSTVHEIL-am (A2-1) and Ac-SALSGHLET-am (A2-2), from annexin A2, and Ac-VKSSSHFNP-am (A8-1), from annexin A8, using UV-vis and circular dichroism (CD) spectroscopies, potentiometry, isothermal titration calorimetry, high-performance liquid chromatography (HPLC), and electrospray ionization mass spectrometry (ESI-MS). We found that at physiological conditions (pH 7.4 and 37 °C) peptides A1-2, A1-3, A8-1, and to some extent A2-2 bind Ni(II) ions sufficiently strongly in 4N complexes and are hydrolyzed at sufficiently high rates to justify the notion that these annexins can undergo nickel hydrolysis in vivo. These results are discussed in the context of specific biochemical interactions of respective proteins. Our results also expand the knowledge about Ni(II) binding to histidine peptides by determination of thermodynamic parameters of this process and spectroscopic characterization of 3N complexes. Altogether, our results indicate that human annexins A1, A2, and A8 are potential molecular targets for nickel toxicity and help design appropriate cellular studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Annexin A1 / chemistry*
  • Annexin A1 / metabolism
  • Annexin A2 / chemistry*
  • Annexin A2 / metabolism
  • Annexins / chemistry
  • Annexins / metabolism
  • Calorimetry
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Humans
  • Hydrolysis
  • Models, Molecular
  • Molecular Sequence Data
  • Nickel / chemistry*
  • Nickel / toxicity*
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Conformation
  • Spectrometry, Mass, Electrospray Ionization
  • Thermodynamics


  • ANXA2 protein, human
  • Annexin A1
  • Annexin A2
  • Annexins
  • Peptide Fragments
  • nickel nitrate
  • Nickel