Transferrin (T) is one of the major protein targets of uranyl (Ur) and the Ur-loaded protein (TUr(2)) interacts with receptor 1. In vitro, Ur is transferred from one of the major plasma complexes, tricarbonated Ur (Ur(CO3)(3)(4-)) to T in four kinetically differentiated steps. The first is very fast and accompanied by HCO3- loss. It yields a first intermediate ternary complex between dicarbonated Ur and the phenolate of one of the two tyrosine ligands in the C-lobe; direct rate constant, k(l) = (7.0 +/- 0.4) x 10(5) M-1 s(-1); reverse rate constant, k(-1) = (4.7 +/- 0.2) x 10(3) M-1 s(-1); dissociation constant, K-1 = (6.7 +/-0.6) x 10(-3) and an affinity of the T for the dicarbonated Ur (Ur(CO3)(2)(2-)) close to that of the latter to CO32-, K-3' similar to 1 x 10(4). This first kinetic product undertakes a fast rate-limiting conformation change leading to the loss of a second HCO3- : direct rate constant, k(2) = 33 +/- 14 s(-1). This second ternary complex undergoes two very slow conformation changes (1 and 5 h), at the end of which both C- and N-lobes become loaded with Ur. When unexposed to uranium, the Ur concentrations in the bloodstream are much too low to favor receptor-mediated transport. However, in the case of exposure, these concentrations can grow considerably. This, added to the fast Ur complex formation with the C-lobe and the fast interaction of the Ur-loaded T with the receptor, can allow a possible internalization by the iron-acquisition pathway.