Self-association and folding in membrane determine the mode of action of peptides from the lytic segment of sticholysins

Ros, Uris; Carretero, Gustavo; Paulino, Joana; Crusca, Edson; Pazos, Fabiola; Cilli, Eduardo Maffud; Lanio, María E.; Schreier, Shirley; Álvarez, Carlos

doi:10.1016/j.biochi.2018.10.005

Cited by 7 publications

(9 citation statements)

References 45 publications

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“…We have previously proposed that the higher permeabilizing activity of StII1-30 could be ascribed to its higher propensity to fold and pre-associate as coiled-coil structures in solution, without the assistance of the membrane (29). The results of this work support the hypothesis that pre-association in solution is an essential prerequisite for the poreforming activity of StII1-30.…”

Section: Discussionsupporting

confidence: 82%

“…Previous structural studies based on low-resolution circular dichroism measurements of StII1-30 have shown that this peptide is able to adopt α-helical secondary structure and self-associate forming coiled-coil structures in solution without the assistance of the membrane (9,29). Therefore, we performed atomistic MD simulations to get preassociated StII1-30 in solution.…”

Section: Iii1 Pre-associated In Solution Stii1-30 Forms Pores In Lipmentioning

confidence: 99%

“…Previously, we have analysed the conformational properties of StI1-31 and StII1-30 in solution and in membrane mimetic systems and their ability to permeabilize lipid vesicles (9,12,13,28,29). In solution, StII1-30 acquires an α-helical fold in coiledcoil self-associated structures, without requiring membrane assistance (29). Based on these findings, we previously suggested a model in which StII1-30 membrane permeabilizing activity is favoured by peptide pre-association in solution.…”

Section: Introductionmentioning

confidence: 97%

“…StII1-30 has emerged as a good candidate to replace the whole toxins in some biomedical applications such as an active component of a vaccinal platform to promote the delivery of different molecules to the cytosol and enhance the immune response in anti-cancer therapies (24,25). Previously, we have analysed the conformational properties of StI1-31 and StII1-30 in solution and in membrane mimetic systems and their ability to permeabilize lipid vesicles (9,12,13,28,29). In solution, StII1-30 acquires an α-helical fold in coiledcoil self-associated structures, without requiring membrane assistance (29).…”

Section: Introductionmentioning

confidence: 99%

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Membrane remodeling by the lytic fragment of sticholysin II: implications for the toroidal pore model

Mesa-Galloso

Valiente

Epand

et al. 2019

Preprint

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Sticholysins are pore-forming toxins of biomedical interest and represent a prototype of proteins acting through the formation of protein-lipid or toroidal pores. Peptides spanning the N-terminus of sticholysins can mimic their permeabilizing activity and together with the full-length toxins have been used as a tool to understand the mechanism of pore formation in membranes. However, the lytic mechanism of these peptides and the lipid shape modulating their activity are not completely clear. In this paper, we combine molecular dynamics (MD) simulations and experimental biophysical tools to dissect different aspects of the pore-forming mechanism of StII1-30, a peptide derived from the N-terminus of sticholysin II. With this combined approach, membrane curvature induction and flip-flop movement of the lipids were identified as two important membrane remodeling steps mediated by StII1-30-pore forming activity.Pore-formation by this peptide was enhanced by the presence of the negatively-curved lipid phosphatidylethanolamine (PE) in membranes. This lipid emerged not only as a facilitator of membrane interactions but also as a structural element of the StII1-30-pore that is recruited to the pore ring upon its assembly. Collectively, these new findings support a toroidal model for the architecture of the pore formed by this peptide and provide new molecular insight into the role of PE as a membrane component that easily accommodates into the ring of toroidal pores aiding in its stabilization. This study contributes to a better understanding of the molecular mechanism underlying the permeabilizing activity of StII1-30 and peptides or proteins acting via a toroidal pore mechanism and offers an informative framework for the optimization of the biomedical application of this and similar molecules.

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Section: Discussionsupporting

confidence: 82%

Section: Iii1 Pre-associated In Solution Stii1-30 Forms Pores In Lipmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Membrane remodeling by the lytic fragment of sticholysin II: implications for the toroidal pore model

Mesa-Galloso

Valiente

Epand

et al. 2019

Preprint

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“…According to the Eisenberg plot [55], NAPHT-BP100 overall hydrophobicity (<H> = 0.409) and significant hydrophobic moment (<µH> = 0.737) classify the peptide-formed helix as "membrane surface seeking". In addition, it has been reported that slight variations in peptide sequence, thus in its hydrophobicity and hydrophobic moment, can trigger considerable changes in the peptide-membrane interaction and permeabilizing capabilities of the peptide [56,57]. Changes in liposome size and size distribution, and zeta potential triggered by NAPHT-BP100 were measured using dynamic light scattering (Figure 7), revealing that membrane charge neutralization plays an important role in membrane destabilization, ultimately causing lipid aggregation.…”

Section: Discussionmentioning

confidence: 97%

Model Membrane Interactions and Biological Activity of a Naphthalimide-Containing BP100

Gpb¹,

Gkv²,

Ma³

et al. 2021

Preprint

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In a large variety of organisms, antimicrobial peptides (AMPs) are primary defences against pathogens. BP100 (KKLFKKILKYL-NH2), a short, synthetic, and cationic AMP, is active against bacteria and displays low toxicity towards eukaryotic cells. BP100 acquires an α-helical conformation upon interaction with membranes and increases membrane permeability. Despite the volume of information available, the mechanism of action of BP100, the selectivity of its biological effects, and its applications are far from consensual. In this work, we synthesized a fluorescent BP100 analog containing naphthalimide linked to its N-terminal end, Napht-BP100 (Napht-AAKKLFKKILKYL-NH2). The fluorescence properties of naphthalimides, especially their spectral sensitivity to microenvironment changes, are well established, and their biological activities against different types of cells are known. A wide variety of techniques were used to demonstrate that a-helical Napht-BP100 was bound and permeabilized POPC and POPG LUV. Napht-BP100, different from that observed for BP100, was bound to, and permeabilized POPC LUV. With zwitterionic (POPC) and negatively charged (POPG) containing LUVs, membrane surface high peptide/lipid ratios triggered complete disruption of the liposomes in a detergent-like manner. This disruption was driven by charge neutralization, lipid aggregation, and membrane destabilization. Napht-BP100 also interacted with double-stranded DNA, indicating that this peptide could also affect other cellular processes in addition to membrane destabilization. Napht-BP100 showed superior antibacterial activity, increased hemolytic activity compared to BP100, and may constitute an efficient antimicrobial agent for dermatological use. By conjugating BP100 and naphthalimide antimicrobial properties, Napht-BP100 was bound more efficiently to the bacterial membrane and could destabilize the membrane and enter the cell by interacting with its cytoplasm- exposed DNA.

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Biophysical approaches to study actinoporin-lipid interactions

Palacios-Ortega

Rivera-de-Torre

Gavilanes

et al. 2021

Methods in Enzymology

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Self-association and folding in membrane determine the mode of action of peptides from the lytic segment of sticholysins

Cited by 7 publications

References 45 publications

Membrane remodeling by the lytic fragment of sticholysin II: implications for the toroidal pore model

Membrane remodeling by the lytic fragment of sticholysin II: implications for the toroidal pore model

Model Membrane Interactions and Biological Activity of a Naphthalimide-Containing BP100

Biophysical approaches to study actinoporin-lipid interactions

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