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Disposal of iron by a mutant form of lipocalin 2.
- Source :
-
Nature communications [Nat Commun] 2016 Oct 31; Vol. 7, pp. 12973. Date of Electronic Publication: 2016 Oct 31. - Publication Year :
- 2016
-
Abstract
- Iron overload damages many organs. Unfortunately, therapeutic iron chelators also have undesired toxicity and may deliver iron to microbes. Here 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 <superscript>-/-</superscript> ) 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.<br />Competing Interests: J.B. and A.Q. declare patent applications with Columbia University for the use of LCN2 (Scn or NGAL). R.K.S., P.B.R. and R.J.A. declare patent applications with Fred Hutchinson Cancer Research Center for the use of Scn (NGAL). All the other authors declare no competing financial interest.
- Subjects :
- Animals
Disease Models, Animal
Humans
Inflammation
Iron Chelating Agents
Iron Overload genetics
Kidney metabolism
Ligands
Mice
Mice, Transgenic
Mutation
Oxidation-Reduction
Protein Binding
Siderophores
Transferrin metabolism
Iron metabolism
Iron Overload metabolism
Lipocalin-2 genetics
Lipocalin-2 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 7
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 27796299
- Full Text :
- https://doi.org/10.1038/ncomms12973