The complex interplay between ligand binding and conformational structure of the folate binding protein (folate...

This review analyzes how interplay between folate binding and changes in folate binding protein (FBP) conformation/self-association affects the biological function of FBP. Concentration-dependent, reversible self-association of hydrophobic apo-FBP at pI=7.4 is associated with decreased affinity for folate, probably due to shielding of binding sites between interacting hydrophobic patches. Titration with folate removes apo-monomers, favoring dissociation of self-associated apo-FBP into apo-monomers. Folate anchors to FBP through a network of hydrogen bonds and hydrophobic interactions, and the binding induces a conformational change with formation of hydrophilic and stable holo-FBP. Holo-FBP exhibits a ligand-mediated concentration-dependent self-association into multimers of great thermal and chemical stability due to strong intermolecular forces. Both ligand and FBP are thus protected against biological/physicochemical decomposition. In biological fluids with low FBP concentrations, e.g., saliva, semen and plasma, hydrophobic apo-monomers and hydrophilic holo-monomers associate into stable asymmetrical complexes with aberrant binding kinetics unless detergents, e.g., cholesterol or phospholipids are present.