The Role of Transferrin in Actinide(IV) Uptake: Comparison with Iron(III)
ABSTRACT The impact of actinides on living organisms has been the subject of numerous studies since the 1950s. From a general point of view, these studies show that actinides are chemical poisons as well as radiological hazards. Actinides in plasma are assumed to be mainly complexed to transferrin, the iron carrier protein. This paper casts light on the uptake of actinides(IV) (thorium, neptunium, plutonium) by transferrin, focusing on the pH dependence of the interaction and on a molecular description of the cation binding site in the protein. Their behavior is compared with that of iron(III), the endogenous transferrin cation, from a structural point of view. Complementary spectroscopic techniques (UV/Vis spectrophotometry, microfiltration coupled with gamma spectrometry, and X-ray absorption fine structure) have been combined in order to propose a structural model for the actinide-binding site in transferrin. Comparison of our results with data available on holotransferrin suggests some similarities between the behavior of Fe(III) and Np(IV)/Pu(IV)/ Np(IV) is not complexed at pH <7, whereas at pH approximately 7.4 complexation can be regarded as quantitative. This pH effect is consistent with the in vivo transferrin "cycle". Pu(IV) also appears to be quantitatively bound by apotransferrin at around pH approximately 7.5, whereas Th(IV) was never complexed under our experimental conditions. EXAFS data at the actinide edge have allowed a structural model of the actinide binding site to be elaborated: at least one tyrosine residue could participate in the actinide coordination sphere (two for iron), forming a mixed hydroxo-transferrin complex in which actinides are bound with transferrin both through An-tyrosine and through An--OH bonds. A description of interatomic distances is provided.
- Gastroenterology 01/2011; 140(5). DOI:10.1016/S0016-5085(11)61685-5 · 13.93 Impact Factor
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ABSTRACT: The understanding of radionuclides (RN) action modes in the living organisms in case of contamination is a major aim in nuclear toxicology studies. The mechanisms of RN-involved toxicity at the molecular level are critically dependent on their speciation. In this framework, the calculating and experimental approaches of speciation determination are described in the first part of this paper. The selection of cobalt, uranium and plutonium as relevant examples of chemical and/or radiotoxic contaminants at diverse levels is further explained. The results regarding their speciation and interactions in various biological media, going from simple biorelevant systems to in vitro and in vivo systems are reported. An interdisciplinary approach, combining i) in silico studies, providing precise aspects of structural insights into protein-RN interactions, ii) in analytico studies, addressing fundamental speciation and structural studies and developments in biorelevant RN-ligands systems, iii) in vitro studies, concerning RN speciation and interactions in cellular systems and iv) in vivo studies describing the RN fate and behavior in part or whole organisms, has been undertaken to explore the results. In each case, the importance of the speciation knowledge is emphasized, in order to shed light on the understanding of RN impact and action modes at the molecular level.Journal of Analytical Atomic Spectrometry 03/2011; 26(3):593-601. DOI:10.1039/C0JA00223B · 3.40 Impact Factor
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ABSTRACT: Plutonium is a toxic synthetic element with no natural biological function, but it is strongly retained by humans when ingested. Using small-angle X-ray scattering, receptor binding assays and synchrotron X-ray fluorescence microscopy, we find that rat adrenal gland (PC12) cells can acquire plutonium in vitro through the major iron acquisition pathway--receptor-mediated endocytosis of the iron transport protein serum transferrin; however, only one form of the plutonium-transferrin complex is active. Low-resolution solution models of plutonium-loaded transferrins derived from small-angle scattering show that only transferrin with plutonium bound in the protein's C-terminal lobe (C-lobe) and iron bound in the N-terminal lobe (N-lobe) (Pu(C)Fe(N)Tf) adopts the proper conformation for recognition by the transferrin receptor protein. Although the metal-binding site in each lobe contains the same donors in the same configuration and both lobes are similar, the differences between transferrin's two lobes act to restrict, but not eliminate, cellular Pu uptake.Nature Chemical Biology 06/2011; 7(8):560-5. DOI:10.1038/nchembio.594 · 13.22 Impact Factor