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

Burton, Mark J.; Kapetanaki, Sofia M.; Chernova, Tatyana; Jamieson, Andrew G.; Dorlet, Pierre; Santolini, Jérôme; Moody, P.C.E.; Mitcheson, John S.; Davies, Noel W.; Schmid, Ralf; Raven, Emma Lloyd; Storey, Nina M.

doi:10.1073/pnas.1600211113

Cited by 56 publications

(58 citation statements)

References 71 publications

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“…The Panx1 channel responds to a variety of physiological stimuli, including low oxygen or shear stress in erythrocytes [4,14,15] and mechanical action on airway epithelial cells [5]. The mechanical stimulation may act directly on the Panx1 protein [13] and deoxygenized heme molecules may activate Panx1 in a similar way as shown previously for the interaction of heme with various other membrane channels [16,17]. Several receptors have been shown to activate Panx1 channel in response to ligand binding.…”

Section: Panx1 Forms a Nonjunctional Membrane Channelmentioning

confidence: 69%

The Pannexin1 membrane channel: distinct conformations and functions

Dahl

2018

FEBS Letters

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The Pannexin1 (Panx1) membrane channel responds to different stimuli with distinct channel conformations. Most stimuli induce a large cation- and ATP-permeable conformation, hence Panx1 is involved in many physiological processes entailing purinergic signaling. For example, oxygen delivery in the peripheral circulatory system is regulated by ATP released from red blood cells and endothelial cells through Panx1 channels. The same membrane channel, however, when stimulated by positive membrane potential or by cleavage with caspase 3, is highly selective for the passage of chloride ions, excluding cations and ATP. Although biophysical data do not allow a distinction between the chloride-selective channels induced by voltage or by caspase cleavage, there must be other subtle differences in the structure, because overexpression of wtPanx1 is well tolerated by cells, while expression of the truncation mutant Panx1Δ378 results in slow cell death. Thus, in addition to the well-characterized two open conformations, there might be a third, more subtle conformational change involved in cell death.

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Section: Panx1 Forms a Nonjunctional Membrane Channelmentioning

confidence: 69%

The Pannexin1 membrane channel: distinct conformations and functions

Dahl

2018

FEBS Letters

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“…1,2 Besides the vitally important catalytic and oxygen transfer functions, compelling evidences have been accumulated in the recent years, which point out that heme, as a regulator molecule, is also involved in numerous cellular and molecular pathways, such as cell proliferation/differentiation, gene transcription/translation, and control of ion channel function. [3][4][5][6][7] However, Abbreviations: CD, circular dichroism; SV, Stern-Volmer the underlying molecular mechanisms by which heme modulates the function of protein targets are poorly understood. From this point of view, the enzymatic degradation products of heme such as biliverdin, the lipophilic bilirubin, and its water soluble conjugate have received much less attention.…”

Section: Introductionmentioning

confidence: 99%

Hemin and bile pigments are the secondary structure regulators of intrinsically disordered antimicrobial peptides

et al. 2017

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The interaction of protoporphyrin compounds of human origin with the major bee venom component melittin (26 a.a., Z +6) and its hybrid derivative (CM15, 15 a.a., Z +6) were studied by a combination of various spectroscopic methods. Throughout a two-state, concentration-dependent process, hemin and its metabolites (biliverdin, bilirubin, bilirubin ditaurate) increase the parallel β-sheet content of the natively unfolded melittin, suggesting the oligomerization of the peptide chains. In contrast, α-helix promoting effect was observed with the also disordered but more cationic CM15. According to fluorescence quenching experiments, the sole Trp residue of melittin is the key player during the binding, in the vicinity of which the first pigment molecule is accommodated presumably making indole-porphyrin π-π stacking interaction. As circular dichroism titration data suggest, cooperative association of additional ligands subsequently occurs, resulting in multimeric complexes with an apparent dissociation constant ranged from 20 to 65 μM. Spectroscopic measurements conducted with the bilirubin catabolite urobilin and stercobilin refer to the requirement of intact dipyrrinone moieties for inducing secondary structure transformations. The binding topography of porphyrin rings on a model parallel β-sheet motif was evaluated by absorption spectroscopy and computational modeling showing a slipped-cofacial binding mode responsible for the red shift and hypochromism of the Soret band. Our results may aid to recognize porphyrin-responsive binding motifs of biologically relevant, intrinsically disordered peptides and proteins, where transient conformations play a vital role in their functions.

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“…62, 63 For instance, binding of heme to His and Cys residues on a cytoplasmic CXXHX 16 H motif of cardiac K ATP channels results in increased currents. 63 Heme increases K ATP currents in a dose-dependent manner with a maximal response achieved with 500 nM heme, and the half-maximal increase in K ATP channel open probability was achieved with ~100 nM heme. These regulatory concentrations of heme are in the physiological range of cytosolic LH, found to be ~20–40 nM using heme sensors HS1-M7A and CISDY.…”

Section: Nature Of Heme Signalingmentioning

confidence: 99%

Heme Gazing: Illuminating Eukaryotic Heme Trafficking, Dynamics, and Signaling with Fluorescent Heme Sensors

2017

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Heme (iron protoporphyrin IX) is an essential protein prosthetic group and signaling molecule required for most life on Earth. All heme-dependent processes require the dynamic and rapid mobilization of heme from sites of synthesis or uptake to hemoproteins present in virtually every subcellular compartment. The cytotoxicity and hydrophobicity of heme necessitate that heme mobilization be carefully controlled to mitigate the deleterious effects of this essential toxin. Indeed, a number of disorders, including certain cancers, cardiovascular diseases, and aging and age-related neurodegenerative diseases, are tied to defects in heme homeostasis. However, the molecules and mechanisms that mediate heme transport and trafficking, and the dynamics of these processes, are poorly understood. This is in large part due to the lack of physical tools for probing cellular heme. Herein, we discuss the recent development of fluorescent probes that can monitor and image kinetically labile heme with respect to its mobilization and role in signaling. In particular, we will highlight how heme gazing with these tools can uncover new heme trafficking factors upon being integrated with genetic screens and illuminate the concentration, subcellular distribution, and dynamics of labile heme in various physiological contexts. Altogether, the monitoring of labile heme, along with recent biochemical and cell biological studies demonstrating the reversible regulation of certain cellular processes by heme, is challenging us to reconceptualize heme from being a static cofactor buried in protein active sites to a dynamic and mobile signaling molecule.

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

Cited by 56 publications

References 71 publications

The Pannexin1 membrane channel: distinct conformations and functions

The Pannexin1 membrane channel: distinct conformations and functions

Hemin and bile pigments are the secondary structure regulators of intrinsically disordered antimicrobial peptides

Heme Gazing: Illuminating Eukaryotic Heme Trafficking, Dynamics, and Signaling with Fluorescent Heme Sensors

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