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Elucidation and Control of Actinide Trafficking Pathways in Mammalian Cells

Elucidation and Control of Actinide Trafficking Pathways in Mammalian Cells. Mark P. Jensen Argonne National Lab Chemical Sciences and Engineering Division. Chuan He University of Chicago Department of Chemistry. Sixth Argonne – UChicago – Fermilab Collaboration Meeting, October 12, 2009.

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Elucidation and Control of Actinide Trafficking Pathways in Mammalian Cells

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  1. Elucidation and Control of Actinide Trafficking Pathways in Mammalian Cells Mark P. Jensen Argonne National Lab Chemical Sciences and Engineering Division Chuan He University of Chicago Department of Chemistry Sixth Argonne – UChicago – Fermilab Collaboration Meeting, October 12, 2009

  2. The Nuclear Conundrum • Nuclear Energy is a carbon-free source for 20% of U.S. & world electricity production. • Why not 80%? • Socio-economic reasons • Cost and economic risk • Proliferation of nuclear technology • Public worries about safety • Technical reason • How do we handle the waste?

  3. Actinides? Really? Recognizing metal ions with high selectivity and sensitivity is essential for life. Nature has evolved various metalloproteins to exploit and control metals.

  4. Objectives • Create new ways to efficiently, economically, and safely • handle actinides when they are no longer useful Discover how cells handle toxic human-made metals, the transuranium actinides • Visualize actinide trafficking in cells with X-ray microbeams • Identify individual proteins that bind actinides in mammalian cells • Biochemically and structurally characterize actinide binding by various proteins

  5. Where do Actinides Accumulate in Cells?

  6. Small Angle X-Ray Scattering of Transferrins First Structures of Pu-Containing Proteins One form of transferrin containing both plutonium and iron has the same shape as the native protein, which contains only iron.

  7. Blocking Pu Uptake by Cells Appears Possible Images of rat adrenal gland cells Axes - coordinates in mm “Bad” Plutonium PuCFeNTf “Bad” Plutonium plus 50 uM chloroquine No Plutonium

  8. Could metal-binding proteins be redesigned to bind actinides? NikR NikR is a transcriptional repressor for expression of the nikABCDE operon in the presence of excessive concentrations of intracellular Ni+2 Ref: C. L. Drennan et al, Nat. Struc. Biol., 2003, 10, 794-799 C. L. Drennan et al, PNAS, 2006, 103, 13676-13681

  9. Design of an Actinyl Binding Site MQRVTITLDD DLLETLDSLS QRRGYNNRSE AIRDILRSAL AQEATQQHGT QGFAVLSYVY EHEKRDLASR IVSTQHHHHD LSVATLHVHI NHDDCLEIAV LKGDMGDVQH FADDVIAQRG VRHGHLQCLP KED Mutations: V72 → S V72SC95→ D, H, S V72S C95D H76→ D,E V72S C95S H76→ D,E

  10. Design of an Actinyl Binding Site The Kd of uranyl binding to NikR’ was determined to be 53 nM

  11. Uranyl Binding and Function

  12. Joint Publication S. V. Wegner, H. Boyaci, H. Chen, M. P. Jensen, C. He, Angew. Chem. Int. Ed. (2009), 48, 2339.

  13. Engineer bacteria to uptake, transport and store actinides

  14. Design Peptides that are Selective for Specific Actinides 1 3 5 9 12 LBT: DTNNDGWYEGDELLA

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