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Surfactin is a lipoheptapeptide produced by several Bacillus species and identified for the first time in 1969. At first, the biosynthesis of this remarkable biosurfactant was described in this review. The peptide moiety of the surfactin is synthesized using huge multienzymatic proteins called NonRibosomal Peptide Synthetases. This mechanism is responsible for the peptide biodiversity of the members of the surfactin family. In addition, on the fatty acid side, fifteen different isoforms (from C12 to C17) can be incorporated so increasing the number of the surfactin-like biomolecules. The review also highlights the last development in metabolic modeling and engineering and in synthetic biology to direct surfactin biosynthesis but also to generate novel derivatives. This large set of different biomolecules leads to a broad spectrum of physico-chemical properties and biological activities. The last parts of the review summarized the numerous studies related to the production processes optimization as well as the approaches developed to increase the surfactin productivity of Bacillus cells taking into account the different steps of its biosynthesis from gene transcription to surfactin degradation in the culture medium.

Summary: Human innate immunity to Trypanosoma brucei involves the trypanosome C-terminal kinesin TbKIFC1, which transports internalized trypanolytic factor apolipoprotein L1 (APOL1) within the parasite. We show that TbKIFC1 preferentially associates with cholesterol-containing membranes and is indispensable for mammalian infectivity. Knockdown of TbKIFC1 did not affect trypanosome growth in vitro but rendered the parasites unable to infect mice unless antibody synthesis was compromised. Surface clearance of Variant Surface Glycoprotein (VSG)-antibody complexes was far slower in these cells, which were more susceptible to capture by macrophages. This phenotype was not due to defects in VSG expression or trafficking but to decreased VSG mobility in a less fluid, stiffer surface membrane. This change can be attributed to increased cholesterol level in the surface membrane in TbKIFC1 knockdown cells. Clearance of surface-bound antibodies by T. brucei is therefore essential for infectivity and depends on high membrane fluidity maintained by the cholesterol-trafficking activity of TbKIFC1.

In recent years, the development of new bio-based products for biocontrol has been gaining importance as it contributes to reducing the use of synthetic herbicides in agriculture. Conventional herbicides (i.e., the ones with synthetic molecules) can lead to adverse effects such as human diseases (cancers, neurodegenerative diseases, reproductive perturbations, etc.) but also to disturbing the environment because of their drift in the air, transport throughout aquatic systems and persistence across different environments. The use of natural molecules seems to be a very good alternative for maintaining productive agriculture but without the negative side effects of synthetic herbicides. In this context, essential oils and their components are increasingly studied in order to produce several categories of biopesticides thanks to their well-known biocidal activities. However, these molecules can also be potentially hazardous to humans and the environment. This article reviews the state of the literature and regulations with regard to the potential risks related to the use of essential oils as bioherbicides in agricultural and horticultural applications.

Natural phytotoxic compounds could become an alternative to traditional herbicides in the framework of sustainable agriculture. Nonanoic acid, sarmentine and sorgoleone are such molecules extracted from plants and able to inhibit the growth of various plant species. However, their mode of action is not fully understood and despite clues indicating that they could affect the plant plasma membrane, molecular details of such phenomenon are lacking. In this paper, we investigate the interactions between those natural herbicides and artificial bilayers mimicking the plant plasma membrane. First, their ability to affect lipid order and fluidity is evaluated by means of fluorescence measurements. It appears that sorgoleone has a clear ordering effect on lipid bilayers, while nonanoic acid and sarmentine induce no or little change to these parameters. Then, a thermodynamic characterization of interactions of each compound with lipid vesicles is obtained with isothermal titration calorimetry, and their respective affinity for bilayers is found to be ranked as follows: sorgoleone > sarmentine > nonanoic acid. Finally, molecular dynamics simulations give molecular details about the location of each compound within a lipid bilayer and confirm the rigidifying effect of sorgoleone. Data also suggest that mismatch in alkyl chain length between nonanoic acid or sarmentine and lipid hydrophobic tails could be responsible for bilayer destabilization. Results are discussed regarding their implications for the phytotoxicity of these compounds.

Understanding the mode of action of membrane contact sites (MCSs) across eukaryotic organisms at the near-atomic level to infer function at the cellular and tissue levels is a challenge scientists are currently facing. These peculiar systems dedicated to inter-organellar communication are perfect examples of cellular processes where the interplay between lipids and proteins is critical. In this mini review, we underline the link between membrane lipid environment, the recruitment of proteins at specialized membrane domains and the function of MCSs. More precisely, we want to give insights on the crucial role of lipids in defining the specificity of plant endoplasmic reticulum (ER)-plasma membrane (PM) MCSs and we further propose approaches to study them at multiple scales. Our goal is not so much to go into detailed description of MCSs, as there are numerous focused reviews on the subject, but rather try to pinpoint the critical elements defining those structures and give an original point of view by considering the subject from a near-atomic angle with a focus on lipids. We review current knowledge as to how lipids can define MCS territories, play a role in the recruitment and function of the MCS-associated proteins and in turn, how the lipid environment can be modified by proteins.

Some amphiphilic molecules are able to interact with the lipid matrix of plant plasma membranes and trigger the immune response in plants. This original mode of perception is not yet fully understood and biophysical approaches could help to obtain molecular insights. In this review, we focus on such membrane-interacting molecules, and present biophysically grounded methods that are used and are particularly interesting in the investigation of this mode of perception. Rather than going into overly technical details, the aim of this review was to provide to readers with a plant biochemistry background a good overview of how biophysics can help to study molecular interactions between bioactive amphiphilic molecules and plant lipid membranes. In particular, we present the biomimetic membrane models typically used, solid-state nuclear magnetic resonance, molecular modeling, and fluorescence approaches, because they are especially suitable for this field of research. For each technique, we provide a brief description, a few case studies, and the inherent limitations, so non-specialists can gain a good grasp on how they could extend their toolbox and/or could apply new techniques to study amphiphilic bioactive compound and lipid interactions.

Saponins are plant secondary metabolites. There are associated with defensive roles due to their cytotoxicity and are active against microorganisms. Saponins are frequently targeted to develop efficient drugs. Plant biomass containing saponins deserves sustained interest to develop high-added value applications. A key issue when considering the use of saponins for human healthcare is their toxicity that must be modulated before envisaging any biomedical application. This can only go through understanding the saponin-membrane interactions. Quinoa is abundantly consumed worldwide, but the quinoa husk is discarded due to its astringent taste associated with its saponin content. Here, we focus on the saponins of the quinoa husk extract (QE). We qualitatively and quantitively characterized the QE saponins using mass spectrometry. They are bidesmosidic molecules, with two oligosaccharidic chains appended on the aglycone with two different linkages; a glycosidic bond and an ester function. The latter can be hydrolyzed to prepare monodesmosidic molecules. The microwave-assisted hydrolysis reaction was optimized to produce monodesmosidic saponins. The membranolytic activity of the saponins was assayed based on their hemolytic activity that was shown to be drastically increased upon hydrolysis. In silico investigations confirmed that the monodesmosidic saponins interact preferentially with a model phospholipid bilayer, explaining the measured increased hemolytic activity.

The use of chemical herbicides could not only potentially induce negative impacts on the environment, animals, and human health, but also increase the weed resistance to herbicides. In this context, the use of plant extracts could be an interesting and natural alternative to chemical products. It is important to understand the mode of action of their bioactive compounds. This is why we have studied the herbicidal effect of Cynara cardunculus crude extract in terms of inhibition of weeds’ seedling growth and its impact on physiological parameters of treated plantlets, like conductivity, dry weight, and fluorescence, and biochemical parameters linked to oxidative stress. We have observed that C. cardunculus crude extract induces oxidative stress in the treated plants and consequently disturbs the physiological and biochemical functions of the plant cells. We have investigated the herbicidal activity of three bioactive compounds, naringenin, myricitrin, and quercetin, from the C. cardunculus crude extract. In both pre- and post-emergence trials, naringenin and myricitrin were significantly more phytotoxic than quercetin. We suggest that their differential initial interaction with the plant’s plasma membrane could be one of the main signals for electrolyte leakage and production of high levels of phenoxyl radicals.

Plasma Membrane is the primary structure for adjusting to ever changing conditions. PM sub-compartmentalization in domains is thought to orchestrate signaling. Yet, mechanisms governing membrane organization are mostly uncharacterized. The plant-specific REMORINs are proteins regulating hormonal crosstalk and host invasion. REMs are the best-characterized nanodomain markers via an uncharacterized moiety called REMORIN C-terminal Anchor. By coupling biophysical methods, super-resolution microscopy and physiology, we decipher an original mechanism regulating the dynamic and organization of nanodomains. We showed that targeting of REMORINis independent of the COP-II-dependent secretory pathway and mediated by PI4P and sterol. REM-CA is an unconventional lipid-binding motif that confers nanodomain organization. Analyzes of REM-CA mutants by single particle tracking demonstrate that mobility and supramolecular organization are critical for immunity. This study provides a unique mechanistic insight into how the tight control of spatial segregation is critical in the definition of PM domain necessary to support biological function.

Since the 50’s, the massive and “environmental naïve” use of synthetic chemistry has revolutionized the farming community facing the dramatic growth of demography. However, nowadays, the controversy grows regarding the long-term harmful effects of these products on human health and the environment. In this context, the use of essential oils (EOs) could be an alternative to chemical products and a better understanding of their mode of biological action for new and optimal applications is of importance. Indeed, if the biocidal effects of some EOs or their components have been at least partly elucidated at the molecular level, very little is currently known regarding their mechanism of action as herbicides at the molecular level. Here, we showed that cinnamon and Java citronella essential oils and some of their main components, i.e.,, cinnamaldehyde (CIN), citronellal (CitA), and citronellol (CitO) could act as efficient herbicides when spread on A. thaliana leaves. The individual EO molecules are small amphiphiles, allowing for them to cross the mesh of cell wall and directly interact with the plant plasma membrane (PPM), which is one of the potential cellular targets of EOs. Hence, we investigated and characterized their interaction with biomimetic PPM while using an integrative biophysical approach. If CitO and CitA, maintaining a similar chemical structure, are able to interact with the model membranes without permeabilizing effect, CIN belonging to the phenylpropanoid family, is not. We suggested that different mechanisms of action for the two types of molecules can occur: while the monoterpenes could disturb the lipid organization and/or domain formation, the phenylpropanoid CIN could interact with membrane receptors.

The olfactory sense is the dominant sensory perception for many animals. When Richard Axel and Linda B. Buck received the Nobel Prize in 2004 for discovering the G protein-coupled receptors’ role in olfactory cells, they highlighted the importance of olfaction to the scientific community. Several theories have tried to explain how cells are able to distinguish such a wide variety of odorant molecules in a complex context in which enantiomers can result in completely different perceptions and structurally different molecules. Moreover, sex, age, cultural origin, and individual differences contribute to odor perception variations that complicate the picture. In this article, recent advances in olfaction theory are presented, and future trends in human olfaction such as structure-based odor prediction and artificial sniffing are discussed at the frontiers of chemistry, physiology, neurobiology, and machine learning.

Molecular Dynamics is a method of choice for membrane simulations and the rising of coarse-grained forcefields has opened the way to longer simulations with reduced calculations times. Here, we present an elastic network, SAHBNET (Surface Accessibility Hydrogen-Bonds elastic NETwork), that will maintain the structure of soluble or membrane proteins based on the hydrogen bonds present in the atomistic structure and the proximity between buried residues. This network is applied on the coarse-grained beads defined by the MARTINI model, and was designed to be more physics-based than a simple elastic network. The SAHBNET model is evaluated against atomistic simulations, and compared with ELNEDYN models. The SAHBNET is then used to simulate two membrane proteins inserted in complex lipid bilayers. These bilayers are formed by self-assembly and the use of a modified version of the GROMACS tool genbox (which is accessible through the gcgs.gembloux.ulg.ac.be website). The results show that SAHBNET keeps the structure close to the atomistic one and is successfully used for the simulation of membrane proteins.

By manipulating the various physicochemical properties of amino acids, the design of peptides with specific self-assembling properties has been emerging for more than a decade. In this context, short peptides possessing detergent properties (so-called “peptergents”) have been developed to self-assemble into well-ordered nanostructures that can stabilize membrane proteins for crystallization. In this study, the peptide with “peptergency” properties, called ADA8 and extensively described by Tao et al., is studied by molecular dynamic simulations for its self-assembling properties in different conditions. In water, it spontaneously forms beta sheets with a β barrel-like structure. We next simulated the interaction of this peptide with a membrane protein, the bacteriorhodopsin, in the presence or absence of a micelle of dodecylphosphocholine. According to the literature, the peptergent ADA8 is thought to generate a belt of β structures around the hydrophobic helical domain that could help stabilize purified membrane proteins. Molecular dynamic simulations are here used to image this mechanism and provide further molecular details for the replacement of detergent molecules around the protein. In addition, we generalized this behavior by designing an amphipathic peptide with beta propensity, which was called ABZ12. Both peptides are able to surround the membrane protein and displace surfactant molecules. To our best knowledge, this is the first molecular mechanism proposed for “peptergency”.

We have identified a G-to-A transition in exon 3 of the APOC3 gene resulting in a novel Ala23Thr apolipoprotein (apo) C-III variant, associated with apoC-III deficiency in three unrelated Yucatan Indians. The Ala23Thr substitution modifies the hydrophobic/hydrophilic repartition of the helical N-terminal peptide and hence could disturb the lipid association. In vitro expression in Escherichia coli of wild-type and mutant apoC-III enabled the characterization of the variant. Compared with wild-type apoC-III-Ala23, the mutant apoC-III-Thr23 showed reduced affinity for dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles with higher amounts of free apoC-III. Displacement of apoE from discoidal apoE:dipalmitoylphosphatidycholine (DPPC) complex by apoC-III-Thr23 was comparable to wild type but the less efficient binding of the apoC-III-Thr23 to the discoidal complex resulted in a higher apoE/apoC-III (mol/mol) ratio (34%) than with wild-type/apoE:DPPC mixtures. The inhibition of lipoprotein lipase (LPL) by apoC-III-Thr23 was comparable to that of wild type, and therefore effects on LPL activity could not explain the lower triglyceride (Tg) levels in Thr-23 carriers. Thus, these in vitro results suggest that in vivo the less efficient lipid binding of apoC-III-Thr23 might lead to a faster catabolism of free apoC-III, reflected in the reduced plasma apoC-III levels identified in Thr-23 carriers, and poorer competition with apoE, which might enhance clearance of Tg-rich lipoproteins and lower plasma Tg levels seen in Thr-23 carriers.—Liu, H., C. Labeur, C-F. Xu, R. Ferrell, L. Lins, R. Brasseur, M. Rosseneu, K. M. Weiss, S. E. Humphries, and P. J. Talmud. Characterization of the lipid-binding properties and lipoprotein lipase inhibition of a novel apolipoprotein C-III variant Ala23Thr. J. Lipid Res. 2000. 41: 1760–1771.

Apolipoprotein L-I (apoL1) is a human-specific serum protein that kills Trypanosoma brucei through ionic pore formation in endosomal membranes of the parasite. The T. brucei subspecies rhodesiense and gambiense resist this lytic activity and can infect humans, causing sleeping sickness. In the case of T. b. rhodesiense, resistance to lysis involves interaction of the Serum Resistance-Associated (SRA) protein with the C-terminal helix of apoL1. We undertook a mutational and deletional analysis of the C-terminal helix of apoL1 to investigate the linkage between interaction with SRA and lytic potential for different T. brucei subspecies. We confirm that the C-terminal helix is the SRA-interacting domain. Although in E. coli this domain was dispensable for ionic pore-forming activity, its interaction with SRA resulted in inhibition of this activity. Different mutations affecting the C-terminal helix reduced the interaction of apoL1 with SRA. However, mutants in the L370-L392 leucine zipper also lost in vitro trypanolytic activity. Truncating and/or mutating the C-terminal sequence of human apoL1 like that of apoL1-like sequences of Papio anubis resulted in both loss of interaction with SRA and acquired ability to efficiently kill human serum-resistant T. b. rhodesiense parasites, in vitro as well as in transgenic mice. These findings demonstrate that SRA interaction with the C-terminal helix of apoL1 inhibits its pore-forming activity and determines resistance of T. b. rhodesiense to human serum. In addition, they provide a possible explanation for the ability of Papio serum to kill T. b. rhodesiense, and offer a perspective to generate transgenic cattle resistant to both T. b. brucei and T. b. rhodesiense.

BACKGROUND: During their blood meal, ticks secrete a wide variety of proteins that interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: Screening a cDNA library in association with RT-PCR and RACE methodologies allowed us to identify 14 new lipocalin genes in the salivary glands of the Ixodes ricinus hard tick. A computational in-depth structural analysis confirmed that LIRs belong to the lipocalin family. These proteins were called LIR for "Lipocalin from I. ricinus" and numbered from 1 to 14 (LIR1 to LIR14). According to their percentage identity/similarity, LIR proteins may be assigned to 6 distinct phylogenetic groups. The mature proteins have calculated pM and pI varying from 21.8 kDa to 37.2 kDa and from 4.45 to 9.57 respectively. In a western blot analysis, all recombinant LIRs appeared as a series of thin bands at 50-70 kDa, suggesting extensive glycosylation, which was experimentally confirmed by treatment with N-glycosidase F. In addition, the in vivo expression analysis of LIRs in I. ricinus, examined by RT-PCR, showed homogeneous expression profiles for certain phylogenetic groups and relatively heterogeneous profiles for other groups. Finally, we demonstrated that LIR6 codes for a protein that specifically binds leukotriene B4. CONCLUSIONS/SIGNIFICANCE: This work confirms that, regarding their biochemical properties, expression profile, and sequence signature, lipocalins in Ixodes hard tick genus, and more specifically in the Ixodes ricinus species, are segregated into distinct phylogenetic groups suggesting potential distinct function. This was particularly demonstrated by the ability of LIR6 to scavenge leukotriene B4. The other LIRs did not bind any of the ligands tested, such as 5-hydroxytryptamine, ADP, norepinephrine, platelet activating factor, prostaglandins D2 and E2, and finally leukotrienes B4 and C4.

BACKGROUND: During their blood meal, ticks secrete a wide variety of proteins that can interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: We previously identified 14 new lipocalin genes in the tick Ixodes ricinus. One of them codes for a protein that specifically binds leukotriene B4 with a very high affinity (Kd: +/-1 nM), similar to that of the neutrophil transmembrane receptor BLT1. By in silico approaches, we modeled the 3D structure of the protein and the binding of LTB4 into the ligand pocket. This protein, called Ir-LBP, inhibits neutrophil chemotaxis in vitro and delays LTB4-induced apoptosis. Ir-LBP also inhibits the host inflammatory response in vivo by decreasing the number and activation of neutrophils located at the tick bite site. Thus, Ir-LBP participates in the tick's ability to interfere with proper neutrophil function in inflammation. CONCLUSIONS/SIGNIFICANCE: These elements suggest that Ir-LBP is a "scavenger" of LTB4, which, in combination with other factors, such as histamine-binding proteins or proteins inhibiting the classical or alternative complement pathways, permits the tick to properly manage its blood meal. Moreover, with regard to its properties, Ir-LBP could possibly be used as a therapeutic tool for illnesses associated with an increased LTB4 production.