5JR8

Disposal of Iron by a Mutant form of Siderocalin NGAL

Summary for 5JR8

• Entry DOI: 10.2210/pdb5jr8/pdb
• Descriptor: Neutrophil gelatinase-associated lipocalin, PHOSPHATE ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: fe-siderophore binding protein mutant, siderophore binding protein
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted : P80188
• Total number of polymer chains: 2
• Total formula weight: 41144.68

Authors

Rupert, P.B.,Strong, R.K.,Barasch, J.,Hollman, M.,Deng, R.,Hod, E.A.,Abergel, R.,Allred, B.,Xu, K.,Darrah, S.,Tekabe, Y.,Perlstein, A.,Bruck, E.,Stauber, J.,Corbin, K.,Buchen, C.,Slavkovich, V.,Graziano, J.,Spitalnik, S.,Qiu, A. (deposition date: 2016-05-05, release date: 2016-09-28, Last modification date: 2024-11-13)

Primary citation

Barasch, J.,Hollmen, M.,Deng, R.,Hod, E.A.,Rupert, P.B.,Abergel, R.J.,Allred, B.E.,Xu, K.,Darrah, S.F.,Tekabe, Y.,Perlstein, A.,Wax, R.,Bruck, E.,Stauber, J.,Corbin, K.A.,Buchen, C.,Slavkovich, V.,Graziano, J.,Spitalnik, S.L.,Bao, G.,Strong, R.K.,Qiu, A.
Disposal of iron by a mutant form of lipocalin 2.
Nat Commun, 7:12973-12973, 2016

PubMed 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) 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.

PubMed: 27796299
DOI: 10.1038/ncomms12973

Experimental method

X-RAY DIFFRACTION (2.65 Å)