Xenon-inhibition of the MscL mechano-sensitive channel and the CopB copper ATPase under different conditions suggests direct effects on these proteins

Petrov, Evgeny; Menon, Gopalakrishnan; Rohde, Paul R.; Battle, Andrew R.; Martinac, Boris; Solioz, Marc

doi:10.1371/journal.pone.0198110

Cited by 8 publications

(8 citation statements)

References 51 publications

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“…Xenon's biological effects were studied previously in numerous animal models (rat, dog, rabbit, etc. ), 35−39 bacteria, 40 cancer cells, 41 kidney cells, 42 neurons, 43,44 and human volunteers. 45,46 Although carried out in a different model system, our studies find protein targets that overlap with previously established modes of action for xenon, specifically xenon's ability to inhibit or influence the activity of proteins with ATP-dependent activity.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Actin is known to polymerize in response to xenon's influence on kinase signaling pathways and heat shock proteins in myocardial cells. 55,56 Other experiments that study xenon's mode of action have implicated xenon's direct interaction with, and influence over, the activity of multiple proteins with ATP-dependent activity, including Enterococcus hirae CopB ATPase 40 and adenosine triphosphate-sensitive potassium (K ATP ) channels present in the brain. 47−50 In our work, we find significant Xe-induced stability changes, or conformational changes, in multiple ATPase pumps including plasma membrane ATPase 1 (PMA1), a hydrogen ion pump; multiple subunits of the Vtype ATPase (VMA1 and VMA2), a proton pump present in vacuolar membrane vesicles; and the alpha subunit of ATP synthase (ATP1), a proton pump present in the mitochondrial membrane.…”

Section: ■ Discussionmentioning

confidence: 99%

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Discovery of the Xenon–Protein Interactome Using Large-Scale Measurements of Protein Folding and Stability

et al. 2022

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The intermolecular interactions of noble gases in biological systems are associated with numerous biochemical responses, including apoptosis, inflammation, anesthesia, analgesia, and neuroprotection. The molecular modes of action underlying these responses are largely unknown. This is in large part due to the limited experimental techniques to study protein–gas interactions. The few techniques that are amenable to such studies are relatively low-throughput and require large amounts of purified proteins. Thus, they do not enable the large-scale analyses that are useful for protein target discovery. Here, we report the application of stability of proteins from rates of oxidation (SPROX) and limited proteolysis (LiP) methodologies to detect protein–xenon interactions on the proteomic scale using protein folding stability measurements. Over 5000 methionine-containing peptides and over 5000 semi-tryptic peptides, mapping to ∼1500 and ∼950 proteins, respectively, in the yeast proteome, were assayed for Xe-interacting activity using the SPROX and LiP techniques. The SPROX and LiP analyses identified 31 and 60 Xe-interacting proteins, respectively, none of which were previously known to bind Xe. A bioinformatics analysis of the proteomic results revealed that these Xe-interacting proteins were enriched in those involved in ATP-driven processes. A fraction of the protein targets that were identified are tied to previously established modes of action related to xenon’s anesthetic and organoprotective properties. These results enrich our knowledge and understanding of biologically relevant xenon interactions. The sample preparation protocols and analytical methodologies developed here for xenon are also generally applicable to the discovery of a wide range of other protein–gas interactions in complex biological mixtures, such as cell lysates.

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Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Discovery of the Xenon–Protein Interactome Using Large-Scale Measurements of Protein Folding and Stability

et al. 2022

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“…Unfortunately, there are no known endogenous ligands or specific toxins targeting MscL that could be useful for the study of chemical structures that directly bind to and modulate MscL gating. However, some chemicals, such as a spider toxin that intercalates in the membrane and modifies several MS channels (192), and even xenon gas (193), which can modify many membrane proteins, have been found to modulate MscL activity. In addition, gadolinium has been shown to inhibit the vast majority of mechanosensitive channels, including MscL, but appears to do so by altering the packing of negatively charged lipids (194).…”

Section: Mscl As a Drug Target Rationale For Targeting Msclmentioning

confidence: 99%

Life with Bacterial Mechanosensitive Channels, from Discovery to Physiology to Pharmacological Target

Blount

Iscla

2020

Microbiol Mol Biol Rev

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SUMMARY General principles in biology have often been elucidated from the study of bacteria. This is true for the bacterial mechanosensitive channel of large conductance, MscL, the channel highlighted in this review. This channel functions as a last-ditch emergency release valve discharging cytoplasmic solutes upon decreases in osmotic environment. Opening the largest gated pore, MscL passes molecules up to 30 Å in diameter; exaggerated conformational changes yield advantages for study, including in vivo assays. MscL contains structural/functional themes that recur in higher organisms and help elucidate how other, structurally more complex, channels function. These features of MscL include (i) the ability to directly sense, and respond to, biophysical changes in the membrane, (ii) an α helix (“slide helix”) or series of charges (“knot in a rope”) at the cytoplasmic membrane boundary to guide transmembrane movements, and (iii) important subunit interfaces that, when disrupted, appear to cause the channel to gate inappropriately. MscL may also have medical applications: the modality of the MscL channel can be changed, suggesting its use as a triggered nanovalve in nanodevices, including those for drug targeting. In addition, recent studies have shown that the antibiotic streptomycin opens MscL and uses it as one of the primary paths to the cytoplasm. Moreover, the recent identification and study of novel specific agonist compounds demonstrate that the channel is a valid drug target. Such compounds may serve as novel-acting antibiotics and adjuvants, a way of permeabilizing the bacterial cell membrane and, thus, increasing the potency of commonly used antibiotics.

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“…To date, Xe has been reported to bind to a wide range of sites in proteins; the best characterized are small hydrophobic cavities . These weak but specific Xe binding interactions exert inhibitory effects on different types of proteins, e.g., xenon inhibition of membrane-bound NMDA receptors is the primary cause of Xe anesthesia. , Other membrane proteins including GLIC and MscL mechano-sensitive channel also demonstrate inhibition by Xe as evidenced by 2-electrode voltage clamping and patch clamping . In addition, Xe inhibits various enzymes, such as CopB copper ATPase, and pepsin as evidenced by colorimetric activity-based assays. , Xenon achieves many useful and interesting biological effects, and the potential for additional clinical applications motivates greater molecular-level understanding of Xe–protein interactions.…”

Section: Introductionmentioning

confidence: 99%

Local Xenon–Protein Interaction Produces Global Conformational Change and Allosteric Inhibition in Lysozyme

Dmochowski

2023

Biochemistry

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Noble gases have well-established biological effects, yet their molecular mechanisms remain poorly understood. Here, we investigated, both experimentally and computationally, the molecular modes of xenon (Xe) action in bacteriophage T4 lysozyme (T4L). By combining indirect gassing methods with a colorimetric lysozyme activity assay, a reversible, Xe-specific (20 ± 3)% inhibition effect was observed. Accelerated molecular dynamic simulations revealed that Xe exerts allosteric inhibition on the protein by expanding a C-terminal hydrophobic cavity. Xe-induced cavity expansion results in global conformational changes, with long-range transduction distorting the active site where peptidoglycan binds. Interestingly, the peptide substrate binding site that enables lysozyme specificity does not change conformation. Two T4L mutants designed to reshape the C-terminal Xe cavity established a correlation between cavity expansion and enzyme inhibition. This work also highlights the use of Xe flooding simulations to identify new cryptic binding pockets. These results enrich our understanding of Xe–protein interactions at the molecular level and inspire further biochemical investigations with noble gases.

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Xenon-inhibition of the MscL mechano-sensitive channel and the CopB copper ATPase under different conditions suggests direct effects on these proteins

Cited by 8 publications

References 51 publications

Discovery of the Xenon–Protein Interactome Using Large-Scale Measurements of Protein Folding and Stability

Discovery of the Xenon–Protein Interactome Using Large-Scale Measurements of Protein Folding and Stability

Life with Bacterial Mechanosensitive Channels, from Discovery to Physiology to Pharmacological Target

Local Xenon–Protein Interaction Produces Global Conformational Change and Allosteric Inhibition in Lysozyme

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