Heme-based sensors: defining characteristics, recent developments, and regulatory hypotheses

Gilles-Gonzalez, Marie Alda; González, Gonzalo

doi:10.1016/j.jinorgbio.2004.11.006

Cited by 314 publications

(267 citation statements)

References 117 publications

(335 reference statements)

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“…HNgb is the first reported sensor that consists of a single globin domain alone, although some globin-coupled sensors in which globin domains are fused to methyl-accepting chemotaxis protein domains or domains for second-messenger regulation have been reported (55). It should be also noted that the function of Ngb proteins has been changing dynamically throughout the evolution of life.…”

Section: Discussionmentioning

confidence: 99%

Human Neuroglobin Functions as an Oxidative Stress-responsive Sensor for Neuroprotection

Watanabe

Takahashi

Uchida

et al. 2012

Journal of Biological Chemistry

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Background: Mammalian neuroglobin (Ngb) is involved in neuroprotection under oxidative stress conditions. Results: Only under oxidative stress, human Ngb was recruited to lipid rafts by interacting with flotillin-1 and suppressed the activation of G␣ i/o by acting as its guanine nucleotide dissociation inhibitor. Conclusion: Human Ngb acts as an intracellular oxidative stress-responsive sensor to protect against cell death. Significance: The neuroprotective mechanism of human Ngb was revealed.

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Section: Discussionmentioning

confidence: 99%

Human Neuroglobin Functions as an Oxidative Stress-responsive Sensor for Neuroprotection

Watanabe

Takahashi

Uchida

et al. 2012

Journal of Biological Chemistry

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“…Inhibition of channel activity as heme concentration increases is consistent with other observations (41) in which knockdown of heme oxygenase (which would increase heme concentration) also reduces channel activity. (C) In the Kv1.4 channel (23), heme binds to the "ball-andchain" N terminus of the A-type potassium channel and impairs the inactivation process; a heme-responsive CXXHX 18 H motif is suggested as being responsible for heme binding, which introduces a stable configuration in the otherwise disordered region. The membrane is depicted in pale blue and the intracellular side is on the bottom.…”

Section: Methodsmentioning

confidence: 99%

“…In all three channels, we note that the heme interacts with a cytoplasmic domain to modulate channel activity, and, in each case, the heme is suggested to bind to a flexible region of protein structure. Thus, for the K ATP channels, heme binds to the CXXHX 16 H motif in the cytoplasmic domain of SUR2A; for the Slo1 (BK) channels, heme binds to the cytochrome c-like CXXCH motif in the conformationally mobile region between RCK1 and RCK2 domains; and for the Kv1.4 channel, heme is suggested to bind to a similar CXXHX 18 H motif close to the N-terminal ball-and-chain inactivation domain, which introduces a stable configuration in an otherwise flexible region. Our results indicate that heme binding increases the open channel probability in K ATP channels, but for BK channels the opposite effect is observed and for the Kv 1.4 channels heme binding impairs channel inactivation.…”

Section: Consideration Of Heme-dependent Regulatory Mechanisms Acrossmentioning

confidence: 99%

A heme-binding domain controls regulation of ATP-dependent potassium channels

Burton

Kapetanaki

Chernova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Heme iron has many and varied roles in biology. Most commonly it binds as a prosthetic group to proteins, and it has been widely supposed and amply demonstrated that subtle variations in the protein structure around the heme, including the heme ligands, are used to control the reactivity of the metal ion. However, the role of heme in biology now appears to also include a regulatory responsibility in the cell; this includes regulation of ion channel function. In this work, we show that cardiac K ATP channels are regulated by heme. We identify a cytoplasmic heme-binding CXXHX 16 H motif on the sulphonylurea receptor subunit of the channel, and mutagenesis together with quantitative and spectroscopic analyses of heme-binding and single channel experiments identified Cys628 and His648 as important for heme binding. We discuss the wider implications of these findings and we use the information to present hypotheses for mechanisms of heme-dependent regulation across other ion channels.heme | heme regulation | K ATP channel | SUR2A | potassium channel

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“…In conclusion, NO is the specific and unique signal required for DNR function; this selective activation in response to a particular ligand is shared with other haem-based gas sensors (e.g. CooA and H-NOX domains) (Andrew et al, 2001;Boon & Marletta, 2005;Gilles-Gonzalez & Gonzalez, 2005). …”

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confidence: 89%

The transcription factor DNR from Pseudomonas aeruginosa specifically requires nitric oxide and haem for the activation of a target promoter in Escherichia coli

et al. 2009

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Pseudomonas aeruginosa is a well-known pathogen in chronic respiratory diseases such as cystic fibrosis. Infectivity of P. aeruginosa is related to the ability to grow under oxygen-limited conditions using the anaerobic metabolism of denitrification, in which nitrate is reduced to dinitrogen via nitric oxide (NO). Denitrification is activated by a cascade of redox-sensitive transcription factors, among which is the DNR regulator, sensitive to nitrogen oxides. To gain further insight into the mechanism of NO-sensing by DNR, we have developed an Escherichia coli-based reporter system to investigate different aspects of DNR activity. In E. coli DNR responds to NO, as shown by its ability to transactivate the P. aeruginosa norCB promoter. The direct binding of DNR to the target DNA is required, since mutations in the helix-turn-helix domain of DNR and specific nucleotide substitutions in the consensus sequence of the norCB promoter abolish the transcriptional activity. Using an E. coli strain deficient in haem biosynthesis, we have also confirmed that haem is required in vivo for the NO-dependent DNR activity, in agreement with the property of DNR to bind haem in vitro. Finally, we have shown, we believe for the first time, that DNR is able to discriminate in vivo between different diatomic signal molecules, NO and CO, both ligands of the reduced haem iron in vitro, suggesting that DNR responds specifically to NO. INTRODUCTIONPseudomonas aeruginosa is one of the most important opportunistic pathogens; it is a Gram-negative bacterium which colonizes the inflamed lungs of cystic fibrosis patients, causing persistent infections (Yoon et al., 2006). P. aeruginosa is able to grow in the absence of oxygen, through anaerobic metabolism, which is important for infectivity and for the formation of biofilm (Hassett et al., 2002; Barraud et al., 2006), a surface-associated antibioticresistant microbial community (Singh et al., 2000). The molecular race between host and pathogen thus includes strategies that are centred on the ability of P. aeruginosa to survive under oxygen-limited conditions; cells lying near the edge of the mucous layer rapidly deplete oxygen (O 2 ), creating a gradient where O 2 drops to very low levels. Under these microaerobic conditions P. aeruginosa grows in thick biofilms probably employing both microaerobic respiration and the denitrifying redox chain Alvarez-Ortega & Harwood, 2007;Platt et al., 2008). The complete denitrification pathway involves four enzymes: nitrate reductase, nitrite reductase, nitric oxide reductase (NOR) and nitrous oxide reductase, operating sequentially to reduce nitrate to dinitrogen gas via nitrite (NO { 2 ), nitric oxide (NO) and nitrous oxide (N 2 O) (Zumft, 1997). The expression and the activity of the NIR and NOR enzymes are tightly controlled because it is mandatory for the bacteria to keep the concentration of intracellular NO below cytotoxic levels, to limit nitrosative stress.In P. aeruginosa the denitrification pathway is regulated by redox signalling, through a cas...

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Heme-based sensors: defining characteristics, recent developments, and regulatory hypotheses

Cited by 314 publications

References 117 publications

Human Neuroglobin Functions as an Oxidative Stress-responsive Sensor for Neuroprotection

Human Neuroglobin Functions as an Oxidative Stress-responsive Sensor for Neuroprotection

A heme-binding domain controls regulation of ATP-dependent potassium channels

The transcription factor DNR from Pseudomonas aeruginosa specifically requires nitric oxide and haem for the activation of a target promoter in Escherichia coli

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