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Structural Studies of Steap3, the Human Erythroid Ferric Reductase, Suggest a Gating Mechanism for Electron Transfer Across the Endosomal Membrane
Author(s) -
Lawrence C. Martin,
Sendamarai Anoop K.,
Ohgami Robert S.,
Fleming Mark D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.813.16
Subject(s) - endosome , transferrin receptor , oxidoreductase , chemistry , endocytosis , biochemistry , cytosol , dmt1 , transmembrane domain , transferrin , biophysics , cofactor , gating , microbiology and biotechnology , biology , transporter , receptor , enzyme , gene
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. Following acidification within the endosome, iron is released from Tf and reduced from Fe 3+ to Fe 2+ by Steap3, the endosomal erythrocyte ferrireductase. The reduced iron then undergoes transport across the endosomal membrane by divalent metal iron transporter 1 (DMT1). Steap3 is a member of a unique family of metalloreductases. These proteins are comprised of a C‐terminal transmembrane domain thought to coordinate a single intramembrane heme and, with the exception of Steap1, an N‐terminal cytosolic oxidoreductase domain. Cytosolic NADPH and a flavin are used as cofactors, but the NADPH/flavin binding domain differs significantly from those in the bacterial Fre, yeast FRE, plant FRO or GP91 phox families of metalloreductases. Instead, Steap3 shows limited similarity to the F 420 H 2 :NADP + Oxidoreductase from A. fulgidus. We have determined the crystal structure of the Steap3 oxidoreductase domain in the absence and presence of NADPH. These structures suggest a gating mechanism for electron transfer across the endosomal membrane.