The Crystal Structure of Six-transmembrane Epithelial Antigen of the Prostate 4 (Steap4), a Ferri/Cuprireductase, Suggests a Novel Interdomain Flavin-binding Site

Gauss, George H.; Kleven, Mark D.; Sendamarai, Anoop K.; Fleming, Mark D.; Lawrence, C. Martin

doi:10.1074/jbc.m113.479154

Cited by 39 publications

(64 citation statements)

References 72 publications

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“…Interestingly, in Steap3 and its mammalian homologs, only two of these histidine residues are conserved, thus predicting only a single transmembrane heme (2). The crystal structures of the truncated cytoplasmic oxidoreductase domains have been determined for Steap3 and Steap4 (10,11). Their structures are quite similar with a backbone root mean square deviation of 1 Å (11).…”

mentioning

confidence: 67%

“…To characterize the enzymatic activity of full-length Steap3, we first developed a ferric reductase activity assay for the intact protein in isolated membranes (see "Experimental Procedures"). Previous enzymatic assays monitored either cell surface ferric reductase activity (2, 3, 11) or flavin-dependent NADPH oxidase activity in a truncated protein (11). In contrast, this assay follows the formation of the Fe 2ϩ -ferrozine complex ( max ϭ 562 nm) and allows the determination of kinetic constants for the full-length protein upon the addition of cytoplasmic (NADPH and FAD) and extracellular substrates (Fe 3ϩ ).…”

Section: Resultsmentioning

confidence: 99%

“…We measured a K m for FAD in full-length Steap3 of ϳ1 M, which is greater than 2 orders of magnitude lower than the non-physiological flavin K m values (Ͼ100 M) measured for the isolated N-terminal oxidoreductase domains of Steap3 and Steap4 (11). Indeed, the structural and kinetic work on these isolated domains previously suggested that the N-terminal oxidoreductase has only a weak interaction with FAD and other FIGURE 6.…”

Section: Steap3 Transmembrane Domain Binds a Single B-typementioning

confidence: 96%

“…As expected, F 420 H 2 :NADP ϩ oxidoreductase was indeed found to be a structural homolog to the Steap oxidoreductase domain (Steap3 backbone root mean square deviation of 1.44 Å) (10 Although structural studies of the isolated Steap3 and Steap4 oxidoreductase domains failed to identify a flavin binding site, flavin-dependent NADPH oxidase activity was observed for the truncated Steap4 domain (11). However, this truncated construct exhibits extremely high, nonphysiological K m values (Ͼ100 M) for each of the flavins examined (FAD, FMN, and riboflavin).…”

mentioning

confidence: 93%

“…The reaction was initiated by addition of 100 M NADPH. Ferric ion reduction at 37°C and formation of the Fe 2ϩ -ferrozine complex was monitored at 562 nm using a thermostated Varian Cary 50 spectrophotometer using an extinction coefficient for the complex of 27,886 M Ϫ1 cm Ϫ1 (11). In each case, the reported activities are the differences between Steap3-transfected cells and empty vector controls.…”

Section: Methodsmentioning

confidence: 99%

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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

Kleven¹,

Dlakić

Lawrence³

2015

Journal of Biological Chemistry

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confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Steap3 Transmembrane Domain Binds a Single B-typementioning

confidence: 96%

mentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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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

Kleven¹,

Dlakić

Lawrence³

2015

Journal of Biological Chemistry

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Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

Doguer

Collins

2018

Comprehensive Physiology

110

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Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two essential trace minerals have been recognized for many decades, but mechanistic details have been lacking. Investigations in recent years have revealed that copper may positively influence iron homeostasis, and also that iron may antagonize copper metabolism. For example, when body iron stores are low, copper is apparently redistributed to tissues important for regulating iron balance, including enterocytes of upper small bowel, the liver, and blood. Copper in enterocytes may positively influence iron transport, and hepatic copper may enhance biosynthesis of a circulating ferroxidase, ceruloplasmin, which potentiates iron release from stores. Moreover, many intestinal genes related to iron absorption are transactivated by a hypoxia-inducible transcription factor, hypoxia-inducible factor-2α (HIF2α), during iron deficiency. Interestingly, copper influences the DNA-binding activity of the HIF factors, thus further exemplifying how copper may modulate intestinal iron homeostasis. Copper may also alter the activity of the iron-regulatory hormone hepcidin. Furthermore, copper depletion has been noted in iron-loading disorders, such as hereditary hemochromatosis. Copper depletion may also be caused by high-dose iron supplementation, raising concerns particularly in pregnancy when iron supplementation is widely recommended. This review will cover the basic physiology of intestinal iron and copper absorption as well as the metabolism of these minerals in the liver. Also considered in detail will be current experimental work in this field, with a focus on molecular aspects of intestinal and hepatic iron-copper interplay and how this relates to various disease states. © 2018 American Physiological Society. Compr Physiol 8:1433-1461, 2018.

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Hepatic STAMP2 alleviates polychlorinated biphenyl‐induced steatosis and hepatic iron overload in NAFLD models

Kim

Park

et al. 2022

Environmental Toxicology

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Polychlorinated biphenyls (PCBs) have been associated with neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. Although the recent studies have demonstrated that PCB exposure leads to nonalcoholic fatty liver disease (NAFLD), the underlying mechanism has remained unsolved. In this study, we examined the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, and PCB 126 in C57BL/6 mice. Male C57Bl/6 mice were fed a standard diet or a 60% high-fat diet and exposed to Aroclor 1260 (10 mg/kg or 20 mg/kg) or PCB 126 (1 mg/kg or 5 mg/kg) by intraperitoneal injection for a total of four injections (2, 3, 4, and 5 weeks) for 6 weeks. In mice, both Aroclor 1260 and PCB 126-induced liver damage, hepatic steatosis and inflammation. We also observed that PCB exposure-induced hepatic iron overload (HIO). We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable therapeutic target for NAFLD patients. Thus, we further examined whether hepatic STAMP2 is involved in PCB-induced NAFLD. We observed that hepatic STAMP2 was significantly decreased in PCB-induced NAFLD models in vivo and in vitro. Furthermore, overexpression of hepatic STAMP2 using an adenoviral delivery system resulted in improvement of PCB-induced steatosis and HIO in vivo and in vitro. Our findings indicate that enhancing hepatic STAMP2 expression represents a potential therapeutic avenue for the treatment of PCB exposure-induced NAFLD.

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The Crystal Structure of Six-transmembrane Epithelial Antigen of the Prostate 4 (Steap4), a Ferri/Cuprireductase, Suggests a Novel Interdomain Flavin-binding Site

Cited by 39 publications

References 72 publications

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

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

Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

Hepatic STAMP2 alleviates polychlorinated biphenyl‐induced steatosis and hepatic iron overload in NAFLD models

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