2vq3: Difference between revisions

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==Overview==

The ~~reduction~~ of iron is an ~~essential step~~ in the transferrin (Tf) ~~cycle, which is~~ the ~~dominant pathway for iron uptake by red blood~~ cell ~~precursors~~. ~~A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia~~. ~~Using a positional cloning strategy~~, ~~we identified a gene~~, ~~six-transmembrane epithelial antigen of the prostate 3~~ (Steap3), ~~responsible for~~ the iron ~~deficiency anemia~~ in ~~the mouse mutant nm1054~~. Steap3 is ~~expressed highly in hematopoietic tissues~~, ~~colocalizes with~~ the ~~Tf cycle endosome and facilitates Tf-bound iron uptake~~. Steap3 ~~shares~~ homology ~~with F(420)H(2):NADP(+) oxidoreductases found in archaea and bacteria~~, ~~as well as with~~ the ~~yeast FRE family of metalloreductases. Overexpression~~ of Steap3 ~~stimulates~~ the ~~reduction~~ of ~~iron,~~ and ~~mice lacking Steap3~~ are ~~deficient in erythroid ferrireductase activity~~. ~~Taken together~~, ~~these findings indicate that Steap3 is an~~ endosomal ~~ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells~~.

The daily production of 200 billion erythrocytes requires 20 mg of iron, accounting for nearly 80% of the iron demand in humans. Thus, erythroid precursor cells possess an efficient mechanism for iron uptake in which iron loaded transferrin (Tf) binds to the transferrin receptor (TfR) at the cell surface. The Tf:TfR complex then enters the endosome via receptor-mediated endocytosis. Upon endosomal acidification, iron is released from Tf, reduced to Fe(2+) by Steap3, and transported across the endosomal membrane by divalent metal iron transporter 1. Steap3, the major ferrireductase in erythrocyte endosomes, is a member of a unique family of reductases. Steap3 is comprised of an N-terminal cytosolic oxidoreductase domain and a C-terminal heme-containing transmembrane domain. Cytosolic NADPH and a flavin are predicted cofactors, but the NADPH/flavin binding domain differs significantly from those in other eukaryotic reductases. Instead, Steap3 shows remarkable, although limited homology to FNO, an archaeal oxidoreductase. We have determined the crystal structure of the human Steap3 oxidoreductase domain in the absence and presence of NADPH. The structure reveals an FNO-like domain with an unexpected dimer interface and substrate binding sites that are well positioned to direct electron transfer from the cytosol to a heme moiety predicted to be fixed within the transmembrane domain. Here, we discuss possible gating mechanisms for electron transfer across the endosomal membrane.

==About this Structure==

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==Reference==

~~Identification~~ of a ferrireductase ~~required for efficient~~ transferrin~~-dependent iron uptake in erythroid cells~~., Ohgami RS, ~~Campagna DR, Greer EL~~, ~~Antiochos B~~, ~~McDonald~~ A~~, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD, Nat Genet~~. ~~2005 Nov~~;37(11):~~1264~~-9. Epub ~~2005 Oct 16~~. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/~~16227996 16227996~~]

Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle., Sendamarai AK, Ohgami RS, Fleming MD, Lawrence CM, Proc Natl Acad Sci U S A. 2008 May 27;105(21):7410-5. Epub 2008 May 21. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18495927 18495927]

[[Category: Homo sapiens]]

[[Category: Single protein]]

Line 58:

[[Category: Transmembrane]]

[[Category: Transport]]

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@@ Line 13: / Line 13: @@
 ==Overview==
-The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors. A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia. Using a positional cloning strategy, we identified a gene, six-transmembrane epithelial antigen of the prostate 3 (Steap3), responsible for the iron deficiency anemia in the mouse mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake. Steap3 shares homology with F(420)H(2):NADP(+) oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.
+The daily production of 200 billion erythrocytes requires 20 mg of iron, accounting for nearly 80% of the iron demand in humans. Thus, erythroid precursor cells possess an efficient mechanism for iron uptake in which iron loaded transferrin (Tf) binds to the transferrin receptor (TfR) at the cell surface. The Tf:TfR complex then enters the endosome via receptor-mediated endocytosis. Upon endosomal acidification, iron is released from Tf, reduced to Fe(2+) by Steap3, and transported across the endosomal membrane by divalent metal iron transporter 1. Steap3, the major ferrireductase in erythrocyte endosomes, is a member of a unique family of reductases. Steap3 is comprised of an N-terminal cytosolic oxidoreductase domain and a C-terminal heme-containing transmembrane domain. Cytosolic NADPH and a flavin are predicted cofactors, but the NADPH/flavin binding domain differs significantly from those in other eukaryotic reductases. Instead, Steap3 shows remarkable, although limited homology to FNO, an archaeal oxidoreductase. We have determined the crystal structure of the human Steap3 oxidoreductase domain in the absence and presence of NADPH. The structure reveals an FNO-like domain with an unexpected dimer interface and substrate binding sites that are well positioned to direct electron transfer from the cytosol to a heme moiety predicted to be fixed within the transmembrane domain. Here, we discuss possible gating mechanisms for electron transfer across the endosomal membrane.
 ==About this Structure==
@@ Line 19: / Line 19: @@
 ==Reference==
-Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells., Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD, Nat Genet. 2005 Nov;37(11):1264-9. Epub 2005 Oct 16. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16227996 16227996]
+Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle., Sendamarai AK, Ohgami RS, Fleming MD, Lawrence CM, Proc Natl Acad Sci U S A. 2008 May 27;105(21):7410-5. Epub 2008 May 21. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18495927 18495927]
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
@@ Line 58: / Line 58: @@
 [[Category: Transmembrane]]
 [[Category: Transport]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed May  7 08:46:25 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun  4 09:59:49 2008''