Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle.
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.
Sendamarai
Anoop K
AK
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.
Ohgami
Robert S
RS
Fleming
Mark D
MD
Lawrence
C Martin
CM
D001665:Binding Sites; D018797:Cell Cycle Proteins; D003461:Crystallography; D019281:Dimerization; D015672:Erythroid Precursor Cells / Q000201:enzymology; D038181:FMN Reductase / Q000737:chemistry*; D006801:Humans; D009249:NADP / Q000737:chemistry; D015513:Oncogene Proteins / Q000737:chemistry*; D010088:Oxidoreductases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D014168:Transferrin / Q000737:chemistry
D018797:Cell Cycle Proteins; D015513:Oncogene Proteins; D014168:Transferrin; D009249:NADP; D010088:Oxidoreductases; C486677:STEAP3 protein, human; D038181:FMN Reductase; C023903:ferric citrate iron reductase