CcsBA is a cytochrome
            <i>c</i>
            synthetase that also functions in heme transport

Frawley, Elaine R.; Kranz, Robert G.

doi:10.1073/pnas.0903132106

Cited by 70 publications

(161 citation statements)

References 46 publications

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“…Topological studies of CcsBA give results similar to those for the separated CcsB and CcsA, as shown in Fig. 3, with the same caveat discussed above concerning the two hydrophobic patches in CcsA (59). Recently, Frawley and Kranz purified milligram quantities of the CcsBA protein with heme bound (59).…”

Section: System Ii: Ccsb and Ccsa Form A Heme Channel And Cytochrome mentioning

confidence: 55%

“…3, with the same caveat discussed above concerning the two hydrophobic patches in CcsA (59). Recently, Frawley and Kranz purified milligram quantities of the CcsBA protein with heme bound (59). Spectral analyses indicate that this heme is b type and is purified in the reduced state (Fe 2ϩ ).…”

Section: System Ii: Ccsb and Ccsa Form A Heme Channel And Cytochrome mentioning

confidence: 99%

“…The authors of a recent review on the evolution of the three members of this superfamily termed this the "hemehandling protein" family (94). The present review will spotlight the heme molecule as it moves through the systems, including the oxidation-reduction state, and it will include the very recent biochemical and spectroscopic evidence that these proteins do indeed handle heme, using the external histidines as axial ligands (59,125). Our premise is that the WWD domain in each of the three families positions the heme molecule with the two vinyl groups surface exposed for orchestrated reactivity with the interacting partners.…”

Section: Cytochrome C Biogenesis: Three Systems and Some Emerging Spmentioning

confidence: 99%

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CytochromecBiogenesis: Mechanisms for Covalent Modifications and Trafficking of Heme and for Heme-Iron Redox Control

Kranz¹,

Richard-Fogal²,

Taylor

et al. 2009

Microbiol Mol Biol Rev

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235

372

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SUMMARY Heme is the prosthetic group for cytochromes, which are directly involved in oxidation/reduction reactions inside and outside the cell. Many cytochromes contain heme with covalent additions at one or both vinyl groups. These include farnesylation at one vinyl in hemes o and a and thioether linkages to each vinyl in cytochrome c (at CXXCH of the protein). Here we review the mechanisms for these covalent attachments, with emphasis on the three unique cytochrome c assembly pathways called systems I, II, and III. All proteins in system I (called Ccm proteins) and system II (Ccs proteins) are integral membrane proteins. Recent biochemical analyses suggest mechanisms for heme channeling to the outside, heme-iron redox control, and attachment to the CXXCH. For system II, the CcsB and CcsA proteins form a cytochrome c synthetase complex which specifically channels heme to an external heme binding domain; in this conserved tryptophan-rich “WWD domain” (in CcsA), the heme is maintained in the reduced state by two external histidines and then ligated to the CXXCH motif. In system I, a two-step process is described. Step 1 is the CcmABCD-mediated synthesis and release of oxidized holoCcmE (heme in the Fe+3 state). We describe how external histidines in CcmC are involved in heme attachment to CcmE, and the chemical mechanism to form oxidized holoCcmE is discussed. Step 2 includes the CcmFH-mediated reduction (to Fe+2) of holoCcmE and ligation of the heme to CXXCH. The evolutionary and ecological advantages for each system are discussed with respect to iron limitation and oxidizing environments.

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Section: System Ii: Ccsb and Ccsa Form A Heme Channel And Cytochrome mentioning

confidence: 55%

Section: System Ii: Ccsb and Ccsa Form A Heme Channel And Cytochrome mentioning

confidence: 99%

Section: Cytochrome C Biogenesis: Three Systems and Some Emerging Spmentioning

confidence: 99%

See 1 more Smart Citation

CytochromecBiogenesis: Mechanisms for Covalent Modifications and Trafficking of Heme and for Heme-Iron Redox Control

Kranz¹,

Richard-Fogal²,

Taylor

et al. 2009

Microbiol Mol Biol Rev

Self Cite

235

372

View full text Add to dashboard Cite

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“…Recently, it was reported that CcsBA, an integral membrane protein of Helicobacter hepaticus, is involved in heme transport for cytochrome c biogenesis (61). CcsBA has a highly conserved tryptophanrich WWD domain that orients the heme to be translocated in concert with histidine residues.…”

Section: Discussionmentioning

confidence: 99%

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Yang

Philips

Doty

et al. 2010

Journal of Biological Chemistry

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The feline leukemia virus subgroup C receptor (FLVCR) is a heme export protein that is required for proerythroblast survival and facilitates macrophage heme iron recycling. However, its mechanism of heme export and substrate specificity are uncharacterized. Using [55 Fe]heme and the fluorescent heme analog zinc mesoporphyrin, we investigated whether export by FLVCR depends on the availability and avidity of extracellular heme-binding proteins. Export was 100-fold more efficient when the medium contained hemopexin (K d < 1 pM) compared with albumin (K d ‫؍‬ 5 nM) at the same concentration and was not detectable when the medium lacked heme-binding proteins. Besides heme, FLVCR could export other cyclic planar porphyrins, such as protoporphyrin IX and coproporphyrin. However, FLVCR has a narrow substrate range because unconjugated bilirubin, the primary breakdown product of heme, was not transported. As neither protoporphyrin IX nor coproporphyrin export improved with extracellular hemopexin (versus albumin), our observations further suggest that hemopexin, an abundant protein with a serum concentration (6.7-25 M) equivalent to that of the iron transport protein transferrin (22-31 M), by accepting heme from FLVCR and targeting it to the liver, might regulate macrophage heme export and heme iron recycling in vivo. Final studies show that hemopexin directly interacts with FLVCR, which also helps explain why FLVCR, in contrast to some major facilitator superfamily members, does not function as a bidirectional gradient-dependent transporter. Together, these data argue that hemopexin has a role in assuring systemic iron balance during homeostasis in addition to its established role as a scavenger during internal bleeding or hemolysis.The biological roles of heme are diverse and encompass most areas of cell metabolism and gene regulation. Heme serves as a prosthetic group in the hemeproteins, which are involved in crucial biological functions, including oxygen binding (hemoglobin and myoglobin), oxygen metabolism (oxidases, peroxidases, catalases, and hydroxylases), electron transfer (cytochromes) (4), and signal transduction (nitric-oxide synthases) (5). In addition, heme serves as a signaling molecule in erythropoiesis and other physiological systems. Because heme generally signals by binding and inactivating a transcriptional repressor (e.g. Bach1) or translational inhibitor (e.g. heme-regulated inhibitor and thus eIF␣2 kinase), its impact is immediate (6 -8). Perhaps for this reason, heme is utilized in time-sensitive processes, such as the regulation of circadian rhythm (9), N-end rule pathway/protein ubiquitination (10), and globin synthesis. Heme is also required for microRNA processing (11). However, excess free or non-protein-bound heme damages lipid, protein, and DNA through the generation of reactive oxygen species, resulting in cellular injury and death (12). Therefore, free cellular heme levels must be tightly regulated to provide an adequate supply yet avoid heme toxicities (4,(13)(14)(15).Most studies of h...

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“…Some bacteria produce a fusion protein of ResB and ResC as a single large polypeptide. ResBC from Helicobacter hepaticus was analyzed following expression in E. coli and it was found that the protein contained reduced heme (50). Amino acids that are suggested to ligate the heme iron were identified and it was hypothesized that histidine residues form a channel for heme transport across the membrane.…”

Section: Heme Transport and Provisionmentioning

confidence: 99%

Cytochrome c assembly

2013

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Cytochromes c are central proteins in energy transduction processes by virtue of their functions in electron transfer in respiration and photosynthesis. They have heme covalently attached to a characteristic CXXCH motif via protein-catalyzed post-translational modification reactions. Several systems with diverse constituent proteins have been identified in different organisms and are required to perform the heme attachment and associated functions. The necessary steps are translocation of the apocytochrome polypeptide to the site of heme attachment, transport and provision of heme to the appropriate compartment, reduction and chaperoning of the apocytochrome, and finally, formation of the thioether bonds between heme and two cysteines in the cytochrome. Here we summarize the established classical models for these processes and present recent progress in our understanding of the individual steps within the different cytochrome c biogenesis systems. V C 2013 IUBMB Life, 65(3): [209][210][211][212][213][214][215][216] 2013

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CcsBA is a cytochrome c synthetase that also functions in heme transport

Cited by 70 publications

References 46 publications

CytochromecBiogenesis: Mechanisms for Covalent Modifications and Trafficking of Heme and for Heme-Iron Redox Control

CytochromecBiogenesis: Mechanisms for Covalent Modifications and Trafficking of Heme and for Heme-Iron Redox Control

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Cytochrome c assembly

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