TCDB is operated by the Saier Lab Bioinformatics Group

5.B.6 The Transmembrane Epithelial Antigen Protein-3  Ferric Reductase (STEAP) Family 

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 (also called TSAP6), 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 (YedZ). Cytosolic NADPH and a flavin are predicted cofactors, but the NADPH/flavin binding domain differs from those in other eukaryotic reductases. Instead, Steap3 shows limited homology to FNO, an archaeal oxidoreductase. Sendamarai et al. (2008) 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 positioned to direct electron transfer from the cytosol to a heme moiety predicted to be fixed within the transmembrane domain. 

Six-transmembrane epithelial antigen of the prostate 3 (Steap3) is the major ferric reductase in developing erythrocytes. Steap family proteins are defined by a shared transmembrane domain that in Steap3 has been shown to function as a transmembrane electron shuttle, moving cytoplasmic electrons derived from NADPH across the lipid bilayer to the extracellular face where they are used to reduce Fe3+ to Fe2+ and potentially Cu2+ to Cu1+ (Kleven et al. 2015). The cytoplasmic N-terminal oxidoreductase domains of Steap3 and Steap4 are relatively well characterized. High affinity FAD, iron and b-type heme binding sites are in the Steap3 transmembrane domain and Steap3 is functional as a homodimer. It utilizes an intrasubunit electron transfer pathway through the single heme moiety rather than an intersubunit electron pathway through a potential domain-swapped dimer. The sequence motifs in the transmembrane domain that are associated with the FAD and metal binding sites are not only present in Steap2 and Steap4 but also in Steap1 which lacks the N-terminal oxidoreductase domain, suggesting that Steap1 harbors latent oxidoreductase activity (Kleven et al. 2015).

References associated with 5.B.6 family:

Arner, P., B.M. Stenson, E. Dungner, E. Näslund, J. Hoffstedt, M. Ryden, and I. Dahlman. (2008). Expression of six transmembrane protein of prostate 2 in human adipose tissue associates with adiposity and insulin resistance. J Clin Endocrinol Metab 93: 2249-2254. 18381574
Gauss, G.H., M.D. Kleven, A.K. Sendamarai, M.D. Fleming, and C.M. Lawrence. (2013). The crystal structure of six-transmembrane epithelial antigen of the prostate 4 (Steap4), a ferri/cuprireductase, suggests a novel interdomain flavin-binding site. J. Biol. Chem. 288: 20668-20682. 23733181
Hasegawa, H., C. Li, B.M. Alba, D.M. Penny, Z. Xia, M.R. Dayao, P. Li, J. Zhang, J. Zhou, D. Lim, C.M. Murawsky, and A.C. Lim. (2018). Membrane cholesterol modulates STEAP2 conformation during dynamic intracellular trafficking processes leading to broad subcellular distribution. Exp Cell Res 370: 208-226. 29940176
Inoue, A., I. Matsumoto, Y. Tanaka, K. Iwanami, A. Kanamori, N. Ochiai, D. Goto, S. Ito, and T. Sumida. (2009). Tumor necrosis factor α-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis. Arthritis Res Ther 11: R118. 19660107
Kim, H.Y., W.Y. Kwon, J.B. Park, M.H. Lee, Y.J. Oh, S. Suh, Y.H. Baek, J.S. Jeong, and Y.H. Yoo. (2020). Hepatic STAMP2 mediates recombinant FGF21-induced improvement of hepatic iron overload in nonalcoholic fatty liver disease. FASEB J. 34: 12354-12366. 32721044
Kleven, M.D., M. Dlakić, and C.M. Lawrence. (2015). Characterization of a Single b-type Heme, FAD, and Metal Binding Sites in the Transmembrane Domain of Six-transmembrane Epithelial Antigen of the Prostate (STEAP) Family Proteins. J. Biol. Chem. 290: 22558-22569. 26205815
Oosterheert, W. and P. Gros. (2020). Cryo-EM structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1. J. Biol. Chem. [Epub: Ahead of Print] 32409586
Oosterheert, W., L.S. van Bezouwen, R.N.P. Rodenburg, J. Granneman, F. Förster, A. Mattevi, and P. Gros. (2018). Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction. Nat Commun 9: 4337. 30337524
Sendamarai, A.K., R.S. Ohgami, M.D. Fleming, and C.M. Lawrence. (2008). Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle. Proc. Natl. Acad. Sci. USA 105: 7410-7415. 18495927
Tamura, T. and J. Chiba. (2009). STEAP4 regulates focal adhesion kinase activation and CpG motifs within STEAP4 promoter region are frequently methylated in DU145, human androgen-independent prostate cancer cells. Int J Mol Med 24: 599-604. 19787193
Yang, D., G.E. Holt, M.P. Velders, E.D. Kwon, and W.M. Kast. (2001). Murine six-transmembrane epithelial antigen of the prostate, prostate stem cell antigen, and prostate-specific membrane antigen: prostate-specific cell-surface antigens highly expressed in prostate cancer of transgenic adenocarcinoma mouse prostate mice. Cancer Res 61: 5857-5860. 11479226
Zhang, C.M., X. Chi, B. Wang, M. Zhang, Y.H. Ni, R.H. Chen, X.N. Li, and X.R. Guo. (2008). Downregulation of STEAP4, a highly-expressed TNF-α-inducible gene in adipose tissue, is associated with obesity in humans. Acta Pharmacol Sin 29: 587-592. 18430367