High-Affinity Interactions of Beryllium(2+) with Phosphatidylserine Result in a Cross-Linking Effect Reducing Surface Recognition of the Lipid.
Yuri A ErmakovKishore KamarajuAntonina Dunina-BarkovskayaKhava S VishnyakovaYegor E YegorovAndriy AnishkinSergei SukharevPublished in: Biochemistry (2017)
Beryllium has multiple industrial applications, but its manufacture is associated with a serious occupational risk of developing chronic inflammation in the lungs known as berylliosis, or chronic beryllium disease. Although the Be2+-induced abnormal immune responses have recently been linked to a specific MHC-II allele, the nature of long-lasting granulomas is not fully understood. Here we show that Be2+ binds with a micromolar affinity to phosphatidylserine (PS), the major surface marker of apoptotic cells. Isothermal titration calorimetry indicates that, like that of Ca2+, binding of Be2+ to PS liposomes is largely entropically driven, likely by massive desolvation. Be2+ exerts a compacting effect on PS monolayers, suggesting cross-linking through coordination by both phosphates and carboxyls in multiple configurations, which were visualized in molecular dynamics simulations. Electrostatic modification of PS membranes by Be2+ includes complete neutralization of surface charges at ∼30 μM, accompanied by an increase in the boundary dipole potential. The data suggest that Be2+ can displace Ca2+ from the surface of PS, and being coordinated in a tight shell of four oxygens, it can mask headgroups from Ca2+-mediated recognition by PS receptors. Indeed, 48 μM Be2+ added to IC-21 cultured macrophages specifically suppresses binding and engulfment of PS-coated silica beads or aged erythrocytes. We propose that Be2+ adsorption at the surface of apoptotic cells may potentially prevent normal phagocytosis, thus causing accumulation of secondary necrotic foci and the resulting chronic inflammation.
Keyphrases
- molecular dynamics simulations
- induced apoptosis
- cell death
- oxidative stress
- immune response
- cell cycle arrest
- drug delivery
- endothelial cells
- drug induced
- signaling pathway
- machine learning
- high glucose
- heavy metals
- anti inflammatory
- endoplasmic reticulum stress
- climate change
- electronic health record
- dendritic cells
- wastewater treatment
- diabetic rats
- big data
- deep learning
- sleep apnea
- stress induced
- inflammatory response
- positive airway pressure