Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex

Bao, Guan‐Hu; Clifton, Matthew S.; Hoette, Trisha M.; Mori, Kiyoshi; Deng, Shi‐Xian; Qiu, Andong; Viltard, Mélanie; Williams, David Y.; Paragas, Neal; Leete, Thomas; Kulkarni, Ritwij; Li, Xiangpo; Lee, Belinda T.; Kalandadze, Avtandil; Ratner, Adam J.; Pizarro, J.C.; Schmidt‐Ott, Kai M.; Landry, Donald W.; Raymond, Kenneth N.; Strong, Roland K.; Barasch, Jonathan

doi:10.1038/nchembio.402

Cited by 278 publications

(326 citation statements)

References 47 publications

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“…Incorporation of exogenous metal ions or ligands within the protein calyx did not affect the overall structure of the protein, suggesting that Scn might shuttle f-element complexes following an endocytosis pathway similar to that described in the trafficking of ferric ion by the Scn-catechol and Scn-Ent adducts (30). To test this hypothesis, we added the radioactive Scn-[ 238 Pu(Ent)] complex to kidney proximal tubule LLCPK cells and demonstrated 238 Pu uptake over a time course of 8 h (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…The general recognition mechanism of Scn has been extensively studied and is well understood (22,24,(27)(28)(29)(30)(31)(32)(33). Ligands bind in the highly sculpted protein calyx, where the key interaction is through an aryl group binding in a snug pocket between the side chains of K125 and K134, with electrostatic and cation-π interactions to this ring and neighboring ones mediated by the side chains of R81, K124, and K134 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

Allred

Rupert

Gauny

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin-transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein-ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligandbased metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of twostage biomimetic platforms for photoluminescence, separation, and transport applications.actinide transport | siderocalin | protein crystallography | luminescence spectroscopy | antenna effect E vents of the last decade have heightened public concern that radionuclides may be released to the environment either deliberately or accidentally (1, 2), with such events potentially leading to the internal contamination of a large number of individuals. The actinides are all highly radioactive, as are some lanthanide fission products, and many of their isotopes decay by alpha particle emission (3). Once internalized, they are distributed to various tissues with patterns that depend on the chemical and physical form of the contaminant in question (4). The densely ionizing alpha particles emitted by actinides when retained can cause tissue damage and induce cancer in target tissues in a dosedependent manner (5). Sufficiently high radionuclide doses may also cause manifestations of acute radiation syndrome. The tissue distribution of an actinide will therefore determine the pattern of injury observed and its radiological and chemical toxicities may lead to serious adverse health effects (6-8). Although they are known to rapidly circulate and deposit into major organs such as bone, liver, or kidney after contamination (6,(8)(9)(10), the specific molecular mechanisms associated with mammalian uptake of these toxic heavy elements remain largely unexplored. Proposed mammalian actinide acquisition and transport mechanisms have typically focused on proteins that use conserved motifs to directly bind the essential elements iron or calcium (6, 8, 10-...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

Allred

Rupert

Gauny

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Both transferrin and DMT1 proteins are associated with the uptake of transferrin-bound iron. We also observe an increase in the mRNA levels of LCN2, a secreted glycoprotein that sequesters bacterial iron-binding siderophores to limit the bacterial growth (69) and has been implicated as an importer of both non-transferrinbound iron (NTBI) and transferrin-bound iron (70,71). Finally, we observe alteration in the gene expression of ferritin subunits, with up-regulation of FHC and down-regulation of FLC, which is consistent with modulation of the intracellular iron storage machinery (72).…”

Section: Icl-1 Visualizes Changes In Labile Iron Pools In An a Baumamentioning

confidence: 94%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

118

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Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.labile iron | molecular imaging | luciferin | metal homeostasis | infectious disease I ron is an essential mineral for nearly every form of life, owing in large part to its ability to cycle between different oxidation states for processes such as nucleotide synthesis, oxygen transport, and respiration (1, 2). At the same time, the potent redox activity of iron is potentially toxic, particularly in unregulated labile forms that can trigger aberrant production of reactive oxygen species via Fenton chemistry (3). Indeed, iron deficiency remains one of the most common nutritional deficiencies in the world (4), and aberrant iron levels have been linked to various ailments, including cancer (5-7), cardiovascular (8), and neurodegenerative (9) disorders, as well as aging (10). The situation is especially complex in infectious diseases, where the requirement for iron by both host organism and invading pathogen leads to an intricate chemical tug-of-war for this metal nutrient during various stages of the immune response (11,12).The foregoing examples provide motivation for developing technologies to monitor biological iron status, with particular interest in methods to achieve in vivo iron imaging in live animal models that go beyond current state-of-the-art assays that are limited primarily to cell culture specimens. In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for d...

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“…9 It was first described as an acute-phase protein 10 able to bind and sequester bacterial iron-loaded siderophores, thus preventing the growth and dissemination of the infectious agents. 11 In addition, LCN2 has been described also to mediate transferrin-independent iron delivery 12,13 and removal from cells, 14 which is associated with cell proliferation and apoptosis, respectively. Although the pathway through which LCN2 influences cell proliferation remains uncertain, LCN2-mediated apoptosis involves the proapoptotic protein BCL2-like 11 (BCL2L11 or BIM).…”

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confidence: 99%

Lipocalin 2 modulates the cellular response to amyloid beta

et al. 2014

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The production, accumulation and aggregation of amyloid beta (Ab) peptides in Alzheimer's disease (AD) are influenced by different modulators. Among these are iron and iron-related proteins, given their ability to modulate the expression of the amyloid precursor protein and to drive Ab aggregation. Herein, we describe that lipocalin 2 (LCN2), a mammalian acute-phase protein involved in iron homeostasis, is highly produced in response to Ab 1-42 by choroid plexus epithelial cells and astrocytes, but not by microglia or neurons. Although Ab 1-42 stimulation decreases the dehydrogenase activity and survival of wild-type astrocytes, astrocytes lacking the expression of Lcn2 are not affected. This protection results from a lower expression of the proapoptotic gene Bim and a decreased inflammatory response. Altogether, these findings show that Ab toxicity to astrocytes requires LCN2, which represents a novel mechanism to target when addressing AD.

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Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex

Cited by 278 publications

References 47 publications

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Lipocalin 2 modulates the cellular response to amyloid beta

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