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Title: Disposal of iron by a mutant form of lipocalin 2

Abstract

Iron overload damages many organs. Unfortunately, therapeutic iron chelators also have undesired toxicity and may deliver iron to microbes. In this work, we show that a mutant form (K3Cys) of endogenous lipocalin 2 (LCN2) is filtered by the kidney but can bypass sites of megalin-dependent recapture, resulting in urinary excretion. Because K3Cys maintains recognition of its cognate ligand, the iron siderophore enterochelin, this protein can capture and transport iron even in the acidic conditions of urine. Mutant LCN2 strips iron from transferrin and citrate, and delivers it into the urine. In addition, it removes iron from iron overloaded mice, including models of acquired (iron-dextran or stored red blood cells) and primary (Hfe -/-) iron overload. In each case, the mutants reduce redox activity typical of non-transferrin-bound iron. In summary, we present a non-toxic strategy for iron chelation and urinary elimination, based on manipulating an endogenous protein:siderophore:iron clearance pathway.

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [3];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [4] more »;  [2];  [5] « less
  1. Columbia Univ., New York, NY (United States)
  2. Fred Hutchinson Cancer Research Center, Seattle, WA (United States). Basic Sciences Division; Univ. of Washington, Seattle, WA (United States). School of Medicine and Dept. of Biochemistry and Immunology
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Chemical Sciences Division and BioActinide Chemistry Group
  4. Anhui Agricultural Univ., Hefei (China). State Key Lab. of Tea Plant Biology and Utilization and School of Tea and Food Sciences
  5. Columbia Univ., New York, NY (United States); Tongji Univ., Shanghai (China). School of Life Sciences and Technology
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Chemical Sciences, Geosciences & Biosciences Division; March of Dimes, White Plains, NY (United States); American Heart Association (AHA); National Natural Science Foundation of China (NNSFC)
Contributing Org.:
Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Berlin (Germany)
OSTI Identifier:
1458480
Grant/Contract Number:  
AC02-05CH11231; R21 DK091729; R01DK073462; R01DK092684; 14GRNT18840098; 81170654/H0507
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Related Information: © The Author(s) 2016.; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Barasch, Jonathan, Hollmen, Maria, Deng, Rong, Hod, Eldad A., Rupert, Peter B., Abergel, Rebecca J., Allred, Benjamin E., Xu, Katherine, Darrah, Shaun F., Tekabe, Yared, Perlstein, Alan, Wax, Rebecca, Bruck, Efrat, Stauber, Jacob, Corbin, Kaitlyn A., Buchen, Charles, Slavkovich, Vesna, Graziano, Joseph, Spitalnik, Steven L., Bao, Guanhu, Strong, Roland K., and Qiu, Andong. Disposal of iron by a mutant form of lipocalin 2. United States: N. p., 2016. Web. doi:10.1038/ncomms12973.
Barasch, Jonathan, Hollmen, Maria, Deng, Rong, Hod, Eldad A., Rupert, Peter B., Abergel, Rebecca J., Allred, Benjamin E., Xu, Katherine, Darrah, Shaun F., Tekabe, Yared, Perlstein, Alan, Wax, Rebecca, Bruck, Efrat, Stauber, Jacob, Corbin, Kaitlyn A., Buchen, Charles, Slavkovich, Vesna, Graziano, Joseph, Spitalnik, Steven L., Bao, Guanhu, Strong, Roland K., & Qiu, Andong. Disposal of iron by a mutant form of lipocalin 2. United States. doi:10.1038/ncomms12973.
Barasch, Jonathan, Hollmen, Maria, Deng, Rong, Hod, Eldad A., Rupert, Peter B., Abergel, Rebecca J., Allred, Benjamin E., Xu, Katherine, Darrah, Shaun F., Tekabe, Yared, Perlstein, Alan, Wax, Rebecca, Bruck, Efrat, Stauber, Jacob, Corbin, Kaitlyn A., Buchen, Charles, Slavkovich, Vesna, Graziano, Joseph, Spitalnik, Steven L., Bao, Guanhu, Strong, Roland K., and Qiu, Andong. Mon . "Disposal of iron by a mutant form of lipocalin 2". United States. doi:10.1038/ncomms12973. https://www.osti.gov/servlets/purl/1458480.
@article{osti_1458480,
title = {Disposal of iron by a mutant form of lipocalin 2},
author = {Barasch, Jonathan and Hollmen, Maria and Deng, Rong and Hod, Eldad A. and Rupert, Peter B. and Abergel, Rebecca J. and Allred, Benjamin E. and Xu, Katherine and Darrah, Shaun F. and Tekabe, Yared and Perlstein, Alan and Wax, Rebecca and Bruck, Efrat and Stauber, Jacob and Corbin, Kaitlyn A. and Buchen, Charles and Slavkovich, Vesna and Graziano, Joseph and Spitalnik, Steven L. and Bao, Guanhu and Strong, Roland K. and Qiu, Andong},
abstractNote = {Iron overload damages many organs. Unfortunately, therapeutic iron chelators also have undesired toxicity and may deliver iron to microbes. In this work, we show that a mutant form (K3Cys) of endogenous lipocalin 2 (LCN2) is filtered by the kidney but can bypass sites of megalin-dependent recapture, resulting in urinary excretion. Because K3Cys maintains recognition of its cognate ligand, the iron siderophore enterochelin, this protein can capture and transport iron even in the acidic conditions of urine. Mutant LCN2 strips iron from transferrin and citrate, and delivers it into the urine. In addition, it removes iron from iron overloaded mice, including models of acquired (iron-dextran or stored red blood cells) and primary (Hfe-/-) iron overload. In each case, the mutants reduce redox activity typical of non-transferrin-bound iron. In summary, we present a non-toxic strategy for iron chelation and urinary elimination, based on manipulating an endogenous protein:siderophore:iron clearance pathway.},
doi = {10.1038/ncomms12973},
journal = {Nature Communications},
number = ,
volume = 7,
place = {United States},
year = {Mon Oct 31 00:00:00 EDT 2016},
month = {Mon Oct 31 00:00:00 EDT 2016}
}

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Works referenced in this record:

Coot model-building tools for molecular graphics
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