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

ABSTRACT: Membrane-active, basic amphipathic peptides represent a class of biomolecules with diverse functions. Sequentially close protein segments also show similar behaviour in several ways. Here we investigated the effect of the lipid mediator lysophosphatidic acid (LPA) on the conformation of structurally disordered peptides including extracellular antimicrobial peptides (AMPs), and calmodulin-binding motifs derived from cytosolic and membrane target proteins. The interaction with associated LPA resulted in gain of ordered secondary structure elements, which for most cases were previously uncharacteristic of the particular peptide. Results revealed mechanism of the LPA-peptide interactions with regulation of the lipid on peptide conformation and oligomerization in a concentration-dependent manner involving (1) relocation of tryptophan residues into the lipid cluster, (2) multiple contacts between the binding partners dictated by complex driving forces, (3) multiple peptide binding to LPA associates with an affinity in the low micromolar range, and (4) selectivity for LPA compared with structurally related lipids. In line with recent findings showing endogenous molecules inducing structural changes in AMPs, we propose that accumulation of LPA in signalling or pathological processes might modulate host-defense activity or trigger certain processes by direct interaction with cationic amphipathic peptide sequences.

SUBMITTER: Juhasz T

PROVIDER: S-EPMC6162328 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Juhász Tünde T Mihály Judith J Kohut Gergely G Németh Csaba C Liliom Károly K Beke-Somfai Tamás T

Scientific reports 20180928 1

Membrane-active, basic amphipathic peptides represent a class of biomolecules with diverse functions. Sequentially close protein segments also show similar behaviour in several ways. Here we investigated the effect of the lipid mediator lysophosphatidic acid (LPA) on the conformation of structurally disordered peptides including extracellular antimicrobial peptides (AMPs), and calmodulin-binding motifs derived from cytosolic and membrane target proteins. The interaction with associated LPA resul ...[more]

PMID: 30266943

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Project description:The evolution of bonded restorations has undergone great progress over several decades. Nonetheless, life spans of bonded restorations are limited mainly because of the eventual incidence of recurrent caries. Over time, water and waterborne agents (acids, enzymes) degrade the components of the dentin/restoration interface, allowing bacterial colonization and dentin reinfection at the margins of the restoration. We developed a 2-tier protective technology consisting of priming/coating dentin with amphipathic and antimicrobial peptides (AAMPs) to obtain hydrophobic/water-repellent and antibiofilm dentin-resisting recurrent caries around bonded restorations. We tested a series of AAMPs to assess their structure-function relationships as well as the effects of different dentin-conditioning methods on the structural features of AAMP-coated dentin. We found relation between the secondary structure of AAMPs (high portion of β-sheet), the antimicrobial potency of AAMPs, and the AAMPs' ability to form hydrophobic coatings on dentin. We also determined that AAMPs had preferential adsorption on the mineral phase of dentin, which suggested that peptides arrange their cationic and hydrophilic motifs in direct contact with the negatively charged minerals in the hydrophilic dentin. These results led us to explore different dentin-conditioning methods that would increase the mineral/collagen ratio and their effect on AAMP immobilization. We innovatively imaged the spatial distribution of the AAMPs in relation to the dentinal tubules and collagen network using a minimally invasive multimodal imaging technique: multiphoton-second harmonic generation. Using multiphoton-second harmonic generation imaging, we determined that partial deproteinization of dentin increased the amount of immobilized AAMPs as compared with the total etched dentin at the dentin surface and extended deeply around dentinal tubules. Last, we analyzed the release rate of AAMPs from dentin coatings in artificial saliva to predict their stability in the clinical setting. In conclusion, priming dentin with AAMPs is a versatile new approach with potential to fortify the otherwise vulnerable adhesive-based interfaces.

Project description:Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to a greater knowledge of, and potential treatments for, a broad range of diseases. To determine whether molecular simulation is able to generate accurate conformational ensembles of IDPs, we explore the structural landscape of the PLP peptide (an intrinsically disordered region of the proteolipid membrane protein) in aqueous and membrane-mimicking solvents, using replica exchange with solute scaling (REST2), and examine the ability of four force fields (ff14SB, ff14IDPSFF, CHARMM36 and CHARMM36m) to reproduce literature circular dichroism (CD) data. Results from variable temperature (VT) 1H and Rotating frame Overhauser Effect SpectroscopY (ROESY) nuclear magnetic resonance (NMR) experiments are also presented and are consistent with the structural observations obtained from the simulations and CD. We also apply the optimum simulation protocol to TP2 and ONEG (a cell-penetrating peptide (CPP) and a negative control peptide, respectively) to gain insight into the structural differences that may account for the observed difference in their membrane-penetrating abilities. Of the tested force fields, we find that CHARMM36 and CHARMM36m are best suited to the study of IDPs, and accurately predict a disordered to helical conformational transition of the PLP peptide accompanying the change from aqueous to membrane-mimicking solvents. We also identify an α-helical structure of TP2 in the membrane-mimicking solvents and provide a discussion of the mechanistic implications of this observation with reference to the previous literature on the peptide. From these results, we recommend the use of CHARMM36m with the REST2 protocol for the study of environment-specific IDP conformations. We believe that the simulation protocol will allow the study of a broad range of IDPs that undergo conformational transitions in different biological environments.

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

Publications

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

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