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An iron-dependent and transferrin-mediated cellular uptake pathway for plutonium

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) (PuCFeNTf) 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.

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Figure 1: PuCFeNTf is the only Pu–transferrin that binds TR strongly.
Figure 2: Structural models of bovine serum transferrins derived from SAXS show that PuCFeNTf adopts a closed conformation.
Figure 3: PC12 cells take in plutonium as PuCFeNTf.

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Acknowledgements

The work at Argonne National Laboratory, including the use of the Advanced Photon Source, was supported by the US Department of Energy, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357, whereas work at Northwestern University was supported by US National Institutes of Health grants EB002100 and U54CA119341.

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Authors

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M.P.J., D.G.-L. and B.A. carried out the experiments and analyzed the data. T.P., P.G.R. and G.E.W. participated in the cell uptake experiments. T.P., L.S., G.E.W., S.V. and B.L. took part in the SXFM experiments and S.S. assisted with the SAXS measurements. S.S. and S.V. also worked on data reduction and analysis. M.P.J. designed the experiments. M.P.J., D.G.-L., B.A. and L.S. wrote the manuscript with input from all the authors.

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Correspondence to Mark P Jensen.

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Jensen, M., Gorman-Lewis, D., Aryal, B. et al. An iron-dependent and transferrin-mediated cellular uptake pathway for plutonium. Nat Chem Biol 7, 560–565 (2011). https://doi.org/10.1038/nchembio.594

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