Structural variability and functional convergence in lactoferrins

Three-dimensional structure analyses of lactoferrin from several species - human, bovine, buffalo and mare - in different forms such as differic, dicu pric, disamarium, oxalate-substituted diferric, oxalate-substituted dicupri c and apo-lactoferrin have revealed various ways in which protein structure adapts to different structural and functional states. The lactoferrin mole cule folds into two lobes, each of which is further divided into two domain s. The metal-saturated form of lactoferrin adopts a closed conformation in all the species whereas the metal-free form (apo) of human lactoferrin has N-lobe in open conformation and the C-lobe is in closed conformation while in mare lactoferrin, both N- and Globes adopt closed conformations, On furt her extension to transferrins, in duck apo-ovotransferrin, both lobes are f ound in open conformations. Comparison of the differic, dicupric and disama rium lactoferrins has shown that different metals can, through variations i n metal positions, have different stereochemistries and anion coordinations without significant changes in protein structure. Substitutions of oxalate for carbonate as seen in the structure of diferric dioxalate mare lactofer rin and in a hybrid dicupric complex with oxalate in one site in human lact oferrin show that larger anions can be accommodated by small side chain mov ements in the binding site. Lactoferrin also binds two molecules of melanin monomer, indole-5,6-quinone specifically suggesting its role in the mechan ism of melanin polymerization, The multidomain/multilobe nature of lactofer rin also allows rigid body movements. Comparison of human, mare, bovine and buffalo lactoferrins, rabbit serum transferrin and duck ovotransferrin sho ws that the relative orientations of the two lobes in each molecule vary su bstantially. These variations may contribute to differences in their bindin g properties.