Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle
Sendamarai, Anoop Kumar Balakrishnan.
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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 Fe²⁺ by Steap3, and transported across the endosomal membrane by divalent metal ion transporter 1. Steap3 is comprised of an N-terminal cytosolic oxidoreductase domain and a C-terminal heme-containing transmembrane domain. The NADPH/flavin binding domain of Steap3 differs significantly from those in other eukaryotic reductases. 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 (PDB-ID 2vns and 2vq3). The structure of the oxidoreductase domain reveals an unexpected dimmer interface and substrate binding sites that are well positioned to direct electron transfer from the cytosol to a transmembrane heme moiety. Sulfolobus turreted icosahedral virus (STIV) was the first icosahedral virus characterized from an archaeal host. It infects Sulfolobus species that thrive in the acidic hot springs (pH 2-4 and 72-9°C) of Yellowstone National Park. The capsid architecture and the structure of its major capsid protein are very similar to those of the bacteriophage PRD1 and eukaryotic viruses Paramecium bursaria Chlorella virus 1 and adenovirus, suggesting a viral lineage that predates the three domains of life. The turrets found on the capsid of STIV are prominent structures that are expected to be involved in host recognition, DNA delivery and may be involved in DNA packaging during viral particle assembly. STIV proteins A223, C381 and C557 constitute the vertex complex that forms these turrets. We report here the efforts to structurally characterize A223. Fold recognition algorithms predict A223 and C381 to have folds similar to that of P5 vertex protein from PRD1, further supporting the possible evolutionary link. This structural similarity has been exploited in attempts to solve the structure of A223 using Molecular Replacement.