Transferrin receptor 1 (R) and human serum transferrin (T) are the two main actors in iron acquisition by the cell. R binds TFe2 (iron-loaded transferrin), which allows its internalization in the cytoplasm by endocytosis. T also forms complexes with metals other than iron. In order to follow the iron-acquisition pathway, these metals should obey at least two essential rules: (i) formation of a strong complex with T; and (ii) interaction of this complex with R. In the present paper, we propose a general mechanism for the interaction of five metal-loaded Ts [Fe(III), Al(III), Bi(III), Ga(III) and Co(III)] with R and we discuss their potential incorporation by the iron-acquisition pathway. With iron- and cobalt-loaded Ts, the interaction of R takes place in two steps: the first is detected by the T-jump technique and occurs in the 100 μs range, whereas the second is slow and occurs in the hour range. Bi(III)- and Ga(III)-loaded Ts interact with R in a single fast kinetic step, which occurs in the 100–500 μs range. No interaction is detected between R and aluminium-saturated T. The fast steps are ascribed to the interaction of the C-lobe of metal-loaded T with the helical domain of R: dissociation constant, K1, of 0.50±0.07, 0.82±0.25, 4±0.4 and 1.10±0.12 μM for Fe(III), Co(III), Bi(III) and Ga(III) respectively. The second slow steps are ascribed to changes in the conformation of the protein–protein adducts which increase the stability to achieve, at thermodynamic equilibrium, an overall dissociation constant, K1, of 2.3 and 25 nM for Fe(III) and Co(III) respectively. This last step occurs over several hours, whereas endocytosis takes place in several minutes. This implies that metal-loaded Ts are internalized with only the C-lobe interacting with R. This suggests that, despite a lower affinity for R when compared with TFe2, some metal-loaded Ts can compete kinetically with TFe2 for the interaction with R and thus follow the iron-acquisition pathway.

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