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5.B.7 The YedZ (YedZ) Family

YedZ of E. coli has been examined topologically and has 6 TMSs with both the N- and C-termini localized to the cytoplasm (Drew et al. 2002).  von Rozycki et al. 2004 identified homologues of YedZ in bacteria and animals. YedZ homologues exhibit conserved histidyl residues in their transmembrane domains that may function in heme binding. Some of the homologues encoded in the genomes of various bacteria have YedZ domains fused to transport, electron transfer and biogenesis proteins (see Figure 8 in von Rozycki et al. 2004). One of the animal homologues is the 6 TMS epithelial plasma membrane antigen of the prostate (STAMP1) that is overexpressed in prostate cancer. Some animal homologues have YedZ domains fused C-terminal to homologues of NADP oxidoreductases.

YedZ homologues arose by intragenic triplication of a 2 TMS-encoding element. They exhibit statistically significant sequence similarity to two families of putative heme export systems and one family of cytochrome-containing electron carriers and have biogenesis (von Rozycki et al. 2004). YedZ homologues can function as heme-binding proteins that facilitate or regulate oxidoreduction, transmembrane electron flow and transport.  Homologues of YedZ are found in a variety of bacteria, including magnetotactic bacteria and cyanobacteria where YedZ domains are fused C-terminal to magnetosome transporters of the MFS superfamily (TC #2.A.1) and to electron carriers of the DsbD family (TC #5.A.1), respectively.

YedZ homologues are found in animals where one includes a human 6 TMS epithelial plasma membrane antigen that is expressed at high levels in prostate cancer cells (Hubert et al. 1999; Yang et al. 2001). Even more distant homologues may include the transmembrane domain within members of the gp91phox NADPH oxidase associated cytochrome b558 (CytB) family (TC #5.B.2).  Heme-containing transmembrane ferric reductase domains (FRD) are found in both bacterial and eukaryotic proteins including ferric reductases (FRE), and NADPH oxidases (NOX) (von Rozycki et al. 2004). Bacteria contain FRD proteins consisting only of a ferric reductase domain, such as YedZ and short FRE proteins. Full length FRE and NOX enzymes are mostly found in eukaryotes and possess a dehydrogenase domain, allowing them to catalyze electron transfer from cytosolic NADPH to extracellular metal ions (FRE) or oxygen (NOX). Metazoa possess YedZ-related STEAP proteins. Phylogenetic analyses suggests that FRE enzymes appeared early in evolution, followed by a transition towards EF-hand containing NOX enzymes (NOX5- and DUOX-like). NOX enzymes are distinguished from FRE enzymes through a four amino acid motif spanning from transmembrane domain 3 (TM3) to TM4, and YedZ/STEAP proteins are identified by the replacement of the first canonical heme-spanning histidine by a highly conserved arginine (Zhang et al. 2013).

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).  High affinity FAD and iron binding sites and a single b-type heme binding site is present in the Steap3 transmembrane domain. Steap3 is functional as a homodimer and utilizes an intrasubunit electron transfer pathway through the single heme moiety rather than an intersubunit electron pathway through a potential domain-swapped dimer (Kleven et al. 2015). 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.

References associated with 5.B.7 family:

Brokx, S.J., R.A. Rothery, G. Zhang, D.P. Ng, and J.H. Weiner. (2005). Characterization of an Escherichia coli sulfite oxidase homologue reveals the role of a conserved active site cysteine in assembly and function. Biochemistry 44: 10339-10348. 16042411
Drew, D., D. Sjöstrand, J. Nilsson, T. Urbig, C.N. Chin, J.W. de Gier, and G. von Heijne. (2002). Rapid topology mapping of Escherichia coli inner-membrane proteins by prediction and PhoA/GFP fusion analysis. Proc. Natl. Acad. Sci. USA 99: 2690-2695. 11867724
Hubert, R.S., I. Vivanco, E. Chen, S. Rastegar, K. Leong, S.C. Mitchell, R. Madraswala, Y. Zhou, J. Kuo, A.B. Raitano, A. Jakobovits, D.C. Saffran, and D.E. Afar. (1999). STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors. Proc. Natl. Acad. Sci. USA 96: 14523-14528. 10588738
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
Loschi, L., S.J. Brokx, T.L. Hills, G. Zhang, M.G. Bertero, A.L. Lovering, J.H. Weiner, and N.C. Strynadka. (2004). Structural and biochemical identification of a novel bacterial oxidoreductase. J. Biol. Chem. 279: 50391-50400. 15355966
von Rozycki, T., M.R. Yen, E.E. Lende, and M.H. Saier, Jr. (2004). The YedZ family: possible heme binding proteins that can be fused to transporters and electron carriers. J. Mol. Microbiol. Biotechnol. 8: 129-140. 16088215
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, X., K.H. Krause, I. Xenarios, T. Soldati, and B. Boeckmann. (2013). Evolution of the ferric reductase domain (FRD) superfamily: modularity, functional diversification, and signature motifs. PLoS One 8: e58126. 23505460