Be 2+ Causes Hypersensitivity but Mg 2+ and Ca 2+ Do Not─Favorable Metal Coordination Is the Key for Differential Allosteric Modulation and Binding Affinities.

Although the ion selectivity of metalloproteins has been well established, selective metal antigen recognition by immunoproteins remains elusive. One such case is the recognition of the Be 2+ ion against its heavier congeners, Mg 2+ and Ca 2+ , by the human leukocyte antigen immunoprotein (HLA-DP2), leading to immunotoxicity. Integrating with our previous mechanistic study on Be 2+ toxicity, herein, we have explored the basis of characteristic nontoxicity of Mg 2+ and Ca 2+ ions despite their in vivo abundance. The ion binding cleft of the HLA-DP2-peptide complex is composed of four acidic residues, p4D and p7E from the peptide and β26E and β69E from the protein. While the tetrahedral coordination site of the smaller Be 2+ ion is located deep inside the cavity, hexa- to octa-coordination sites of Mg 2+ and Ca 2+ ions are located closer to the protein surface. The intrinsic high coordination number of Mg 2+ /Ca 2+ ions induces allosteric modifications on the HLA-DP2_M2 surface, which are atypical for TCR recognition. Furthermore, the lower binding energy of larger Mg 2+ and Ca 2+ ions with the cavity residues can be correlated to the lower charge density and reduced covalent bonding nature as compared to those of the smaller Be 2+ ion. In short, weak binding of Mg 2+ and Ca 2+ ions and the unfavorable allosteric surface modifications are probably the major determinants for the absence of Mg 2+ /Ca 2+ ion-mediated hypersensitivity in humans.