Structure of the Membrane Proximal Oxioreductase Domain of Human Steap3, the Dominant Ferrireductase of the Erythroid Transferrin Cycle

Journal Article · Wed May 27 04:00:00 EDT 2009 · Proc. Nat. Acad. Sci. 105:7410,2008

OSTI ID:953557

Sendamarai, A K; Ohgami, R S; Fleming, M D; Lawrence, C M

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{sup 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.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953557
• Report Number(s): SLAC-REPRINT-2009-326
• Journal Information: Proc. Nat. Acad. Sci. 105:7410,2008, Journal Name: Proc. Nat. Acad. Sci. 105:7410,2008 Journal Issue: 21 Vol. 105; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
ACCOUNTING
ACIDIFICATION
CRYSTAL STRUCTURE
DEMAND
DIMERS
ELECTRON TRANSFER
ERYTHROCYTES
HEME
INTERFACES
IRON
ISOALLOXAZINES
MEMBRANES
METALS
OXIDOREDUCTASES
Other
OTHER
PRECURSOR
PRODUCTION
RECEPTORS
SUBSTRATES
TRANSFERRIN
UPTAKE