The lipid mediator lysophosphatidic acid induces folding of disordered peptides with basic amphipathic character into rare conformations

Juhász, Tünde; Mihály, Judith; Kohut, Gergely; Németh, Csaba; Liliom, Károly; Beke‐Somfai, Tamás

doi:10.1038/s41598-018-32786-4

Cited by 11 publications

(11 citation statements)

References 53 publications

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“…Compared with anionic lipid DOPG, distinct structural variations caused by uncharged lipid DOPC suggest that charge might play a crucial role in stabilizing the secondary structure of proteins. However, charge distribution along the peptide is also crucial for the interaction between the amyloidogenic peptide and the lipid . Our results also pointed out that CTD of PAP 248‐286 folds mainly to form β‐sheets upon interaction with DOPC.…”

Section: Discussionsupporting

confidence: 56%

The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

Kumar

Gour

Verma

et al. 2019

Journal of Peptide Science

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Seminal amyloids are well known for their role in enhancing HIV infection. Among all the amyloidogenic peptides identified in human semen, PAP 248-286 was found to be the most active and was termed as semen-derived enhancer of viral infection (SEVI). Although amyloidogenic nature of the peptide is mainly linked with enhancement of the viral infection, the most active physiological conformation of the aggregated peptide remains inconclusive. Lipids are known to modulate aggregation pathway of a variety of proteins and peptides and constitute one of the most abundant biomolecules in human semen. PAP 248-286 significantly differs from the other known amyloidogenic peptides, including Aβ and IAPP, in terms of critical concentration, surface charge, fibril morphology, and structural transition during aggregation. Hence, in the present study, we aimed to assess the effect of a lipid, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), on PAP 248-286 aggregation and the consequent conformational outcomes. Our initial observation suggested that the presence of the lipid considerably influenced the aggregation of PAP 248-286 . Further, ZDOCK and MD simulation studies of peptide multimerization have suggested that the hydrophobic residues at C-terminus are crucial for PAP 248-286 aggregation and are anticipated to be major DOPC-interacting partners. Therefore, we further assessed the aggregation behaviour of C-terminal (PAP 273-286 ) fragment of PAP 248-286 and observed that DOPC possesses the ability to interfere with the aggregation behaviour of both the peptides used in the current study. Mechanistically, we propose that the presence of DOPC causes considerable inhibition of the peptide aggregation by interfering with the peptide's disordered state to β-sheet transition.

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Section: Discussionsupporting

confidence: 56%

The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

Kumar

Gour

Verma

et al. 2019

Journal of Peptide Science

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“…Although some have intracellular targets, the action mechanism of most AMPs is based on the disruption of cell membranes (Hancock and Sahl, 2006; Ageitos et al ., 2017). This process is often associated with a disorder-to-order conformational transition upon interaction with lipid membranes (Ageitos et al ., 2017), but also observed for interactions with biomacromolecules (Otvos et al ., 2000; Kragol et al ., 2001; Barańska-Rybak et al ., 2005; Bandyopadhyay et al ., 2013), or even smaller compounds such as endogenous metabolites or drug molecules (Zsila et al ., 2017 a , 2017 b , Juhász et al ., 2018). AMPs often show a broad-spectrum activity toward bacteria, viruses, fungi, protozoa, and even cancer cells (Hancock and Sahl, 2006; Hancock et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

“…However, very little is explored related to the nature of such AMP interactions. It has recently been demonstrated that some biologically active small molecules, such as therapeutic drugs, azo dyes with sulphonyl groups, endogenous molecules, and lipid mediators, are able to affect the secondary structure of AMPs (Zsila et al ., 2017 a , 2017 b , 2019; Juhász et al ., 2018). These compounds induce a disorder-to-order conformational transition similarly to what is regularly observed for AMP–membrane interactions (Ageitos et al ., 2017).…”

Section: Introductionmentioning

confidence: 99%

Anionic food color tartrazine enhances antibacterial efficacy of histatin-derived peptide DHVAR4 by fine-tuning its membrane activity

Ricci

Horváti

Juhász

et al. 2020

Quart. Rev. Biophys.

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Here it is demonstrated how some anionic food additives commonly used in our diet, such as tartrazine (TZ), bind to DHVAR4, an antimicrobial peptide (AMP) derived from oral host defense peptides, resulting in significantly fostered toxic activity against both Gram-positive and Gram-negative bacteria, but not against mammalian cells. Biophysical studies on the DHVAR4–TZ interaction indicate that initially large, positively charged aggregates are formed, but in the presence of lipid bilayers, they rather associate with the membrane surface. In contrast to synergistic effects observed for mixed antibacterial compounds, this is a principally different mechanism, where TZ directly acts on the membrane-associated AMP promoting its biologically active helical conformation. Model vesicle studies show that compared to dye-free DHVAR4, peptide–TZ complexes are more prone to form H-bonds with the phosphate ester moiety of the bilayer head-group region resulting in more controlled bilayer fusion mechanism and concerted severe cell damage. AMPs are considered as promising compounds to combat formidable antibiotic-resistant bacterial infections; however, we know very little on their in vivo actions, especially on how they interact with other chemical agents. The current example illustrates how food dyes can modulate AMP activity, which is hoped to inspire improved therapies against microbial infections in the alimentary tract. Results also imply that the structure and function of natural AMPs could be manipulated by small compounds, which may also offer a new strategic concept for the future design of peptide-based antimicrobials.

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“…Indeed, previous studies in our group have suggested that small molecules of both endogenous and synthetic origin can dramatically affect the structures of AMPs, potentially altering their mechanistic function, including their antimicrobial efficiency . Similarly, it has also been observed that several disordered AMP and protein sequences adopt ordered secondary structures induced by the lipid mediator lysophosphatidic acid; this indicates that the presence and use of such interactions might be widespread in organisms, a phenomenon far from being understood.…”

Section: Introductionmentioning

confidence: 99%

Manipulating Active Structure and Function of Cationic Antimicrobial Peptide CM15 with the Polysulfonated Drug Suramin: A Step Closer to in Vivo Complexity

et al. 2019

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Antimicrobial peptides (AMPs) kill bacteria by targeting their membranes through various mechanisms involving peptide assembly, often coupled with disorder‐to‐order structural transition. However, for several AMPs, similar conformational changes in cases in which small organic compounds of both endogenous and exogenous origin have induced folded peptide conformations have recently been reported. Thus, the function of AMPs and of natural host defence peptides can be significantly affected by the local complex molecular environment in vivo; nonetheless, this area is hardly explored. To address the relevance of such interactions with regard to structure and function, we have tested the effects of the therapeutic drug suramin on the membrane activity and antibacterial efficiency of CM15, a potent hybrid AMP. The results provided insight into a dynamic system in which peptide interaction with lipid bilayers is interfered with by the competitive binding of CM15 to suramin, resulting in an equilibrium dependent on peptide‐to‐drug ratio and vesicle surface charge. In vitro bacterial tests showed that when CM15⋅suramin complex formation dominates over membrane binding, antimicrobial activity is abolished. On the basis of this case study, it is proposed that small‐molecule secondary structure regulators can modify AMP function and that this should be considered and could potentially be exploited in future development of AMP‐based antimicrobial agents.

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The lipid mediator lysophosphatidic acid induces folding of disordered peptides with basic amphipathic character into rare conformations

Cited by 11 publications

References 53 publications

The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

Anionic food color tartrazine enhances antibacterial efficacy of histatin-derived peptide DHVAR4 by fine-tuning its membrane activity

Manipulating Active Structure and Function of Cationic Antimicrobial Peptide CM15 with the Polysulfonated Drug Suramin: A Step Closer to in Vivo Complexity

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