Roles of Magnesium and Simvastatin in Structural Changes, Stability, and Affinity of the Ligand Binding Domain of Integrin αXβ2



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Myeloid leukocytes contribute to inflammatory responses in immune dysregulations such as atherosclerosis, autoimmune encephalomyelitis, and arthritis. Leukocyte integrin, αXβ2 plays a pivotal role in their recruitment from circulation to lesions. Integrin αXβ2, known as a dendritic cell marker and complement receptor 4, is a heterodimeric cell surface receptor that bi-directionally relays cellular signals and functions in cellular trafficking, phagocytosis, and T-cell proliferation. In the regulation of these events, the ligand-binding domain of αXβ2, called the αX I-domain, acts like the gatekeeper of the bidirectional signals and relays them through affinity maturation and conformational changes from the closed to open state. A divalent cation is essential for the αX I-domain interaction with an acidic residue of a ligand. The biophysical approaches discussed here reveal that the addition of Mg2+ results in an alteration of the structure and stability of the αX I-domain in-solution. The multiplicity of the αX I-domain conformations existing in-solution is associated with its affinity regulation to physiological ligands such as fibrinogen and iC3b. The hydrophobic environment in the Metal Ion Dependent Adhesion site (MIDAS), the Mg2+-binding motif, appears to determine the ionization states of two critical MIDAS aspartates, Mg2+ creates a link from MIDAS motif to the allosteric sites, all of which contribute to the integrin activation. The local rearrangements and cation-dependent flexibility of the αX I-domain facilitate affinity maturation. These features support the rapid equilibrium of the αX I-domain between the closed and the open conformations required during rapid leukocyte activation, important for regulating leukocyte adhesiveness and migration.