1 research outputs found
High-Affinity Interactions of Beryllium(2+) with Phosphatidylserine Result in a Cross-Linking Effect Reducing Surface Recognition of the Lipid
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 Be<sup>2+</sup>-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
Be<sup>2+</sup> binds with a micromolar affinity to phosphatidylserine
(PS), the major surface marker of apoptotic cells. Isothermal titration
calorimetry indicates that, like that of Ca<sup>2+</sup>, binding
of Be<sup>2+</sup> to PS liposomes is largely entropically driven,
likely by massive desolvation. Be<sup>2+</sup> 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 Be<sup>2+</sup> includes complete neutralization
of surface charges at ∼30 μM, accompanied by an increase
in the boundary dipole potential. The data suggest that Be<sup>2+</sup> can displace Ca<sup>2+</sup> from the surface of PS, and being coordinated
in a tight shell of four oxygens, it can mask headgroups from Ca<sup>2+</sup>-mediated recognition by PS receptors. Indeed, 48 μM
Be<sup>2+</sup> added to IC-21 cultured macrophages specifically suppresses
binding and engulfment of PS-coated silica beads or aged erythrocytes.
We propose that Be<sup>2+</sup> adsorption at the surface of apoptotic
cells may potentially prevent normal phagocytosis, thus causing accumulation
of secondary necrotic foci and the resulting chronic inflammation