Single-molecule phospholipase A2 becomes processive on melittin-induced membrane deformations

Jepson, Tyler A; Hall, Sarah C.; Chung, Jean K.

doi:10.1016/j.bpj.2022.03.019

Cited by 3 publications

(9 citation statements)

References 46 publications

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“…This results in a significantly longer dwell times, at membrane defects as observed by singlemolecule tracking. 23 The observations presented here of PLA 2 exclusively localized at the phase separation boundaries of the vesicles are consistent with these previous findings.…”

Section: ■ Results and Discussionsupporting

confidence: 93%

“…19−22 In our previous work in solid-supported lipid bilayers using single-molecule tracking, we found that melittin deforms the membrane into island-like structures, and PLA 2 becomes processive at the edge of those structures and shows 25-fold higher apparent activity. 23 These results are consistent with the established notions that melittin disrupts the membrane structure, and PLA 2 becomes active at membrane defects. 24,25 Our findings in giant unilamellar vesicles (GUVs) with the capacity for phase transition reveal an additional dimension of the collaborative effects of melittin and PLA 2 .…”

Section: ■ Introductionsupporting

confidence: 90%

“…Where PLA 2 -AF647 could be found on the vesicles, it was imaged at the boundary of phase separation, but not on the other areas of GUV surfaces (Figure 4A,B). It is well documented that phase transition 40 as well as membrane defects and borders 23,41 promote PLA 2 activation, and hydrolysis occurs predominantly at the domain boundaries. 42,43 The reaction site of phospholipids is buried deep in an intact lipid bilayer.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Melittin–Phospholipase A₂ Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles

Min,

Picou,

Jeong

et al. 2024

Langmuir

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The primary constituents of honeybee venom, melittin and phospholipase A 2 (PLA 2 ), display toxin synergism in which the PLA 2 activity is significantly enhanced by the presence of melittin. It has been shown previously that this is accomplished by the disruption in lipid packing, which allows PLA 2 to become processive on the membrane surface. In this work, we show that melittin is capable of driving miscibility phase transition in giant unilamellar vesicles (GUVs) and that it raises the miscibility transition temperature (T misc ) in a concentration-dependent manner. The induced phase separation enhances the processivity of PLA 2 , particularly at its boundaries, where a substantial difference in domain thickness creates a membrane discontinuity. The catalytic action of PLA 2 , in response, induces changes in the membrane, rendering it more conducive to melittin binding. This, in turn, facilitates further lipid phase separation and eventual vesicle lysis. Overall, our results show that melittin has powerful membrane-altering capabilities that activate PLA 2 in various membrane contexts. More broadly, they exemplify how this biochemical system actively modulates and capitalizes on the spatial distribution of membrane lipids to efficiently achieve its objectives.

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Section: ■ Results and Discussionsupporting

confidence: 93%

Section: ■ Introductionsupporting

confidence: 90%

Section: ■ Results and Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Melittin–Phospholipase A₂ Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles

Min,

Picou,

Jeong

et al. 2024

Langmuir

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“…PLA2 stimulates arachidonic acid production which increases calcium carrying into the beta-cells to provoke insulin secretion (Figure 9b). [30,91] But the major function of PLA2 in the field of lowering blood sugar is increasing glucose uptake into the adipose tissues. One major complication in diabetes is hyperlipidemia.…”

Section: Antidiabetic Effect Of Mltmentioning

confidence: 99%

“…Studies have shown that MLT increases PLA2 activity which protects hepatocytes by inducing the production of anti‐inflammatory cytokines. [ 91 ]…”

Section: Anti‐inflammatory Effects Of Mlt On Various Diseasesmentioning

confidence: 99%

Immunomodulatory activities and biomedical applications of melittin and its recent advances

Jafari,

Sadeghi,

Dehaghi

et al. 2024

Archiv der Pharmazie

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Melittin (MLT), a peptide containing 26 amino acids, is a key constituent of bee venom. It comprises ∼40%–60% of the venom's dry weight and is the main pricing index for bee venom, being the causative factor of pain. The unique properties of MLT extracted from bee venom have made it a very valuable active ingredient in the pharmaceutical industry as this cationic and amphipathic peptide has propitious effects on human health in diverse biological processes. It has the ability to strongly impact the membranes of cells and display hemolytic activity with anticancer characteristics. However, the clinical application of MLT has been limited by its severe hemolytic activity, which poses a challenge for therapeutic use. By employing more efficient mechanisms, such as modifying the MLT sequence, genetic engineering, and nano‐delivery systems, it is anticipated that the limitations posed by MLT can be overcome, thereby enabling its wider application in therapeutic contexts. This review has outlined recent advancements in MLT's nano‐delivery systems and genetically engineered cells expressing MLT and provided an overview of where the MLTMLT's platforms are and where they will go in the future with the challenges ahead. The focus is on exploring how these approaches can overcome the limitations associated with MLT's hemolytic activity and improve its selectivity and efficacy in targeting cancer cells. These advancements hold promise for the creation of innovative and enhanced therapeutic approaches based on MLT for the treatment of cancer.

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Bee Venom: Composition and Anticancer Properties

Gajski,

Leonova,

Sjakste

2024

Toxins

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Among the various natural compounds used in alternative and Oriental medicine, toxins isolated from different organisms have had their application for many years, and Apis mellifera venom has been studied the most extensively. Numerous studies dealing with the positive assets of bee venom (BV) indicated its beneficial properties. The usage of bee products to prevent the occurrence of diseases and for their treatment is often referred to as apitherapy and is based mainly on the experience of the traditional system of medical practice in diverse ethnic communities. Today, a large number of studies are focused on the antitumor effects of BV, which are mainly attributed to its basic polypeptide melittin (MEL). Previous studies have indicated that BV and its major constituent MEL cause a strong toxic effect on different cancer cells, such as liver, lung, bladder, kidney, prostate, breast, and leukemia cells, while a less pronounced effect was observed in normal non-target cells. Their proposed mechanisms of action, such as the effect on proliferation and growth inhibition, cell cycle alterations, and induction of cell death through several cancer cell death mechanisms, are associated with the activation of phospholipase A2 (PLA2), caspases, and matrix metalloproteinases that destroy cancer cells. Numerous cellular effects of BV and MEL need to be elucidated on the molecular level, while the key issue has to do with the trigger of the apoptotic cascade. Apoptosis could be either a consequence of the plasmatic membrane fenestration or the result of the direct interaction of the BV components with pro-apoptotic and anti-apoptotic factors. The interaction of BV peptides and enzymes with the plasma membrane is a crucial step in the whole process. However, before its possible application as a remedy, it is crucial to identify the correct route of exposure and dosage of BV and MEL for potential therapeutic use as well as potential side effects on normal cells and tissues to avoid any possible adverse event.

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Single-molecule phospholipase A2 becomes processive on melittin-induced membrane deformations

Cited by 3 publications

References 46 publications

Melittin–Phospholipase A₂ Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles

Melittin–Phospholipase A₂ Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles

Immunomodulatory activities and biomedical applications of melittin and its recent advances

Bee Venom: Composition and Anticancer Properties

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Single-molecule phospholipase A2 becomes processive on melittin-induced membrane deformations

Cited by 3 publications

References 46 publications

Melittin–Phospholipase A2 Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles

Melittin–Phospholipase A2 Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles

Immunomodulatory activities and biomedical applications of melittin and its recent advances

Bee Venom: Composition and Anticancer Properties

Contact Info

Product

Resources

About

Melittin–Phospholipase A₂ Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles

Melittin–Phospholipase A₂ Synergism Is Mediated by Liquid–Liquid Miscibility Phase Transition in Giant Unilamellar Vesicles