2vns
Crystal Structure of the Membrane Proximal Oxidoreductase Domain of Human Steap3, the Dominant Ferric Reductase of the Erythroid Transferrin Cycle
Structural highlights
FunctionSTEA3_HUMAN Endosomal ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Participates in erythroid iron homeostasis by reducing Fe(3+) to Fe(2+). Can also reduce of Cu(2+) to Cu(1+), suggesting that it participates in copper homeostasis. Uses NADP(+) as acceptor. May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression. Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP.[1] [2] [3] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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. 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:18495927[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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