Cm³⁺/Eu³⁺ induced structural, mechanistic and functional implications for calmodulin

Area of Science:

• Biochemistry
• Computational Chemistry
• Spectroscopy

Background:

• Trivalent actinides and lanthanides pose health risks due to industrial activities like mining.
• These ions exhibit high affinity for calmodulin (CaM), a crucial protein in cellular signaling.
• Inadvertent uptake can lead to protein dysfunction and ion accumulation in human organs.

Purpose of the Study:

• Investigate the effects of An3+ and Ln3+ ion substitution on CaM structure, enzymatic activity, and cytotoxicity.
• Characterize the binding interactions between CaM and Cm3+/Eu3+ ions.
• Understand the molecular mechanisms underlying CaM's response to these toxic metal ions.

Main Methods:

• Spectroscopy
• Computational chemistry (MP2 level, fragment molecular orbital method)
• Calorimetry
• Biochemistry

Main Results:

• Cm3+ and Eu3+ show higher affinity for CaM than Ca2+ across all four binding sites.
• A unique high-affinity site (EF-hand 3) exhibits exothermic binding for Eu3+, while other sites show endothermic binding due to hydration shell loss.
• Binding of Cm3+/Eu3+ causes minor structural disorder in CaM and a slight decrease in enzymatic activity compared to Ca2+-CaM.

Conclusions:

• Cm3+ and Eu3+ bind to CaM with high affinity, with distinct thermodynamic and structural consequences.
• EF-hand 3's unique properties facilitate preferential binding of these trivalent ions.
• The findings provide molecular insights into CaM-actinide/lanthanide interactions, relevant for understanding toxicity and developing mitigation strategies.