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See detailStudy of thermomyces ianuginosa lipase in the presence of tributyrylglycerol and water
Santini, Sébastien; Crowet, Jean-Marc ULg; Thomas, Annick ULg et al

in Biophysical Journal (2009), 96(12), 4814-4825

The Thermomyces lanuginosa lipase has been extensively studied in industrial and biotechnological research because of its potential for triacylglycerol transformation. This protein is known to catalyze ... [more ▼]

The Thermomyces lanuginosa lipase has been extensively studied in industrial and biotechnological research because of its potential for triacylglycerol transformation. This protein is known to catalyze both hydrolysis at high water contents and transesterification in quasi-anhydrous conditions. Here, we investigated the Thermomyces lanuginosa lipase structure in solution in the presence of a tributyrin aggregate using 30 ns molecular-dynamics simulations. The water content of the active-site groove was modified between the runs to focus on the protein-water molecule interactions and their implications for protein structure and protein-lipid interactions. The simulations confirmed the high plasticity of the lid fragment and showed that lipid molecules also bind to a secondary pocket beside the lid. Together, these results strongly suggest that the lid plays a role in the anchoring of the protein to the aggregate. The simulations also revealed the existence of a polar channel that connects the active-site groove to the outside solvent. At the inner extremity of this channel, a tyrosine makes hydrogen bonds with residues interacting with the catalytic triad. This system could function as a pipe (polar channel) controlled by a valve (the tyrosine) that could regulate the water content of the active site. [less ▲]

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See detailDetection and characterization of tilted peptides in amyloid proteins
Crowet, Jean-Marc ULg; Lins, Laurence ULg; Brasseur, Robert ULg

Poster (2009, April 25)

The study of amyloidogenic proteins is of interest in biochemistry because these proteins undergo conformational changes and aggregation. Both processes are largely implicated in several diseases ... [more ▼]

The study of amyloidogenic proteins is of interest in biochemistry because these proteins undergo conformational changes and aggregation. Both processes are largely implicated in several diseases including Alzheimer’s, Parkinson’s or Creutzfeldt-Jakob’s disease. These phenomena are not completely understood, either at a structural or energetical point of view. Tilted peptides are short protein fragment (11 to 19 residues) that adopt a tilted orientation when inserted into biological membranes and destabilise them. Recently, tilted peptides have been detected in two amyloidogenic proteins involved in neurodegenerative diseases; the amyloid  peptide responsible for Alzheimer’s disease, and the PrP protein that causes Creutzfeldt-Jakob’s disease. Tilted peptides could be responsible for the neurotoxic effects of these proteins. Due to their destabilising properties, they could interact directly with the membrane leading to cell death. Tilted peptides could also be involved in the transconformational process of the proteins. The aim of this work is to detect tilted fragments in other amyloidogenic proteins by molecular modelling and to study some of these peptides experimentally to evidence their lipid destabilizing properties, their structure and their toxicity. Twenty-four tilted peptides from 18 different proteins have been detected among 53 amyloidogenic proteins and 7 peptides were tested experimentally. The results support the hypothesis that some tilted peptides could be involved in transconformational processes and/or cytotoxicity related to amyloidogenic proteins. [less ▲]

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See detailPepLook Scale-Up: Prediction of protein structures
Crowet, Jean-Marc ULg; Brasseur, Robert ULg; Lins, Laurence ULg

Conference (2009, January 27)

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See detailC-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.
Lecordier, Laurence; Vanhollebeke, Benoit; Poelvoorde, Philippe et al

in PLoS Pathogens (2009), 5(12), 1000685

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 ... [more ▼]

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. [less ▲]

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See detailExosites Mediate The Anti-Inflammatory Effects Of A Multifunctional Serpin From The Saliva Of The Tick Ixodes Ricinus
Prevot, Pp.; Beschin, A.; Lins, Laurence ULg et al

in Febs Journal (2009), 276(12),

Serine protease inhibitors (serpins) are a structurally related but functionally diverse family of ubiquitous proteins. We previously described Ixodes ricinus immunosuppressor (Iris) as a serpin from the ... [more ▼]

Serine protease inhibitors (serpins) are a structurally related but functionally diverse family of ubiquitous proteins. We previously described Ixodes ricinus immunosuppressor (Iris) as a serpin from the saliva of the tick I. ricinus displaying high affinity for human leukocyte elastase. Iris also displays pleotropic effects because it interferes with both the immune response and hemostasis of the host. It thus inhibits lymphocyte proliferation and the secretion of interferon-gamma or tumor necrosis factor-alpha by peripheral blood mononuclear cells, and also platelet adhesion, coagulation and fibrinolysis. Its ability to interfere with coagulation and fibrinolysis, but not platelet adhesion, depends on the integrity of its antiproteolytic reactive center loop domain. Here, we dissect the mechanisms underlying the interaction of recombinant Iris with peripheral blood mononuclear cells. We show that Iris binds to monocytes/macrophages and inhibits their ability to secrete tumor necrosis factor-alpha. Recombinant Iris also has a protective role in endotoxemic shock. The anti-inflammatory ability of Iris does not depend on its antiprotease activity. Moreover, we pinpoint the exosites involved in this activity. [less ▲]

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See detailStudy of the specific lipid binding properties of Abeta 11-22 fragment at endosomal pH.
Ravault, S.; Flore, Christelle ULg; Saurel, O. et al

in Langmuir (2009), 25(18), 10948-53

Increasing evidence implicates interactions between Abeta peptide and lipids in the development of Alzheimer's disease. More generally, Abeta peptide interactions with membranes seem to depend on the ... [more ▼]

Increasing evidence implicates interactions between Abeta peptide and lipids in the development of Alzheimer's disease. More generally, Abeta peptide interactions with membranes seem to depend on the composition of the lipid bilayer and the structural features of the peptide. One key parameter should be pH, since one site of intracellular Abeta peptide production and/or accumulation is likely to be endosomes. This intracellular endosomal accumulation was suggested to contribute to disease progression. In this paper, we report a study on the 11-22 amphiphilic domain of Abeta in interaction with model membrane; this region contains most of the charged residues of the N-terminal domain of Abeta. We show that the peptide charge, and more precisely the protonation state of histidines 13 and/or 14, is important for the interaction with lipids. Hence, it is only at endosomal pH that a conformational change of the peptide is observed in the presence of negatively charged lipid vesicles, that is, when both lipid headgroups and histidines can interact through electrostatic interactions. Specific interactions of the fragment with phosphatidylserine and to a lesser extent with phosphatidylcholine, but not phosphatidylethanolamine, are further evidenced by the Langmuir monolayer technique. From our results, we suggest that the protonation state of His residues could have a role in the pathogenic surface interaction of the whole Abeta peptide with membranes. [less ▲]

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See detailThe "Tilted Peptide Theory" links membrane insertion properties and fusogenicity of viral fusion peptides.
Charloteaux, Benoît ULg; Lorin, Aurélien; Brasseur, Robert ULg et al

in Protein & Peptide Letters (2009), 16(7), 718-25

Class I fusion glycoproteins of viruses are involved in the fusion between viral envelope and cell membrane. A region located in the N-terminal domain of these glycoproteins, called the fusion peptide, is ... [more ▼]

Class I fusion glycoproteins of viruses are involved in the fusion between viral envelope and cell membrane. A region located in the N-terminal domain of these glycoproteins, called the fusion peptide, is essential for fusion. Fusion peptides are able to induce by themselves in vitro membrane fusion. In this paper, we review the properties of those peptides related to their fusogenicity, in particular the correlation existing between their ability to insert obliquely in membranes and fusogenicity. This relation notably allows predicting successfully the minimal region of some fusion peptides sufficient to induce significant in vitro fusion. The notion of obliquity and fusogenicity is discussed in terms of the existing proposed mechanisms for viral fusion. [less ▲]

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See detailDetermination Of The Minimal Fusion Peptide Of Hiv, Siv And Blv Fusion Glycoproteins
Lorin, A.; Charloteaux, Benoît ULg; Lins, Laurence ULg et al

in Peptides For Youth - the Proceedings of the 20th American Peptidesymposium (2009), 611

The entry of enveloped viruses into target cells requires the fusion between the viral envelope and the target cell membrane. In the case of many viruses like HIV, SIV and BLV, the fusion is mediated by ... [more ▼]

The entry of enveloped viruses into target cells requires the fusion between the viral envelope and the target cell membrane. In the case of many viruses like HIV, SIV and BLV, the fusion is mediated by class 1 fusion glycoproteins located on the viral envelope. These fusion glycoproteins contain a region at their N-terminal extremity called the “fusion peptide”, which interact with the target membrane. Many mutagenesis studies showed that this region is required for mediating membrane fusion [1]. Moreover, synthetic peptides corresponding to the fusion peptide of many glycoproteins induce membrane fusion in vitro. Despite the large number of studies on synthetic fusion peptides, the region necessary and sufficient to induce optimal membrane fusion is not known. To determine this minimal fusion peptide, we used the “tilted peptide” theory. According to this theory, a helical peptide inserting obliquely into membranes induces fusion [2]. Moreover, the more tilted the peptide is, the more important the fusion is. Then, we postulate that the minimal fusion peptide corresponds to the shortest helical fragment able to insert into the membrane with an angle close to 45°. This peptide was predicted using the IMPALA algorithm, which allow to predict peptide-membrane interactions [3]. Fusogenicity of this peptide was then assessed in liposome lipid-mixing and leakage assays and compared to the fusogenicity of smaller and longer peptides to check the validity of the prediction. This methodology was used to determine successfully the minimal fusion peptide of three viruses, HIV, SIV and BLV. [less ▲]

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See detailImpacts of the carbonyl group location of ester bond on interfacial properties of sugar-based surfactants: experimental and computational evidences
Razafindralambo, Hary ULg; Blecker, Christophe ULg; Mezdour, Samir et al

in Journal of Physical Chemistry B (2009), 113

Interfacial properties of surfactants are dependent on the conformation adopted by the hydrophilic headgroup or/and the hydrophobic tail at the boundary limit of two immiscible phases. Here, we ... [more ▼]

Interfacial properties of surfactants are dependent on the conformation adopted by the hydrophilic headgroup or/and the hydrophobic tail at the boundary limit of two immiscible phases. Here, we demonstrate the impacts of the carbonyl group (-CO-) location of the ester bond of sugar-based surfactants by comparing some properties of two closely related esters, octyl glucuronate and glucose octanoate, at the air-water interface. The carbonyl group location influences the rate and extent of interfacial adsorption and the rheology properties of sugar esters at the air-water interface, which were evaluated by dynamic surface tension and complex surface viscoelastic measurements. Octyl glucuronate adsorbs the fastest at the air-water interface whereas glucose octanoate reduces the dynamic surface tension at the lowest value and exhibits the highest film viscoelasticity. Differences are attributed to molecular conformation constraints inducing relevant changes to the surface coverage kinetic capacity and the interaction strengths of the octyl sugar ester adsorbed films at the air-water interface. All of the results are supported by the minimum cross-sectional area values per molecule determined by both experimental and computational approaches. [less ▲]

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See detailImplication of tilted peptides in viral fusion
Lins, Laurence ULg; Brasseur, Robert ULg

Poster (2008, August)

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See detailDéstabilisation membranaire et peptides obliques : état des lieux
Lins, Laurence ULg

Conference (2008, June)

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See detailDéstabilisation membranaire et peptides obliques : état des lieux
Lins, Laurence ULg

Conference (2008, May 13)

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See detailAntiangiogenic peptides
Martial, Joseph ULg; Struman, Ingrid ULg; Nguyen, Ngoc-Quynh-Nhu ULg et al

Patent (2008)

The present invention refers to a pharmaceutical composition comprising an isolated antiangiogenic peptide or a recombinant protein comprising the antiangiogenic peptide, wherein the peptide is between 11 ... [more ▼]

The present invention refers to a pharmaceutical composition comprising an isolated antiangiogenic peptide or a recombinant protein comprising the antiangiogenic peptide, wherein the peptide is between 11 and 40 amino acids in length and having antiangiogenic activity, the peptide comprising the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14, wherein X1 is any amino acid residue comptabile with forming a helix; X2 is an amino acid redisue of : Leu, Ile, Val; X3 is an amino acid residue of: Arg, Lys, His, Ser, Thr; X4 is an amino acid residue of: Ile, Leu, Val; X5 is any amino acid residue compatible with forming a helix; X6 is an amino acid residue of: Leu, Ile, Val; X7 is an amino acid residue of: Leu, Ile, Val, Ser, Thr; X8 is any amino acid residue compatible with forming a helix; X9 is any amino acid residue compatible with forming a helix; X10 is an amino acid residue of: Gln, Glu, Asp, Arg, His, Lys, Asn; X11 is an amino acid residue of: Ser, Thr; X12 is an amino acid residue of: Trp, Tyr, Phe; X13 is an animo acid residue of Leu, Ile, Val, Asn, Gln; X14 is an amino acid residue of: Glu, Gln, Asp, Asn. [less ▲]

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See detailIxodes ricinus Tick Lipocalins: Identification, Cloning, Phylogenetic Analysis and Biochemical Characterization
Beaufays, Jérôme ULg; Adam, Benoit; Decrem, Yves et al

in PLoS ONE (2008), 3(12), 3941

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 ... [more ▼]

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. [less ▲]

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See detailDistantly related lipocalins share two conserved clusters of hydrophobic residues: use in homology modeling.
Adam, Benoit; Charloteaux, Benoît ULg; Beaufays, Jérôme ULg et al

in BMC structural biology (2008), 8(1-2), 1-18

BACKGROUND: Lipocalins are widely distributed in nature and are found in bacteria, plants, arthropoda and vertebra. In hematophagous arthropods, they are implicated in the successful accomplishment of the ... [more ▼]

BACKGROUND: Lipocalins are widely distributed in nature and are found in bacteria, plants, arthropoda and vertebra. In hematophagous arthropods, they are implicated in the successful accomplishment of the blood meal, interfering with platelet aggregation, blood coagulation and inflammation and in the transmission of disease parasites such as Trypanosoma cruzi and Borrelia burgdorferi. The pairwise sequence identity is low among this family, often below 30%, despite a well conserved tertiary structure. Under the 30% identity threshold, alignment methods do not correctly assign and align proteins. The only safe way to assign a sequence to that family is by experimental determination. However, these procedures are long and costly and cannot always be applied. A way to circumvent the experimental approach is sequence and structure analyze. To further help in that task, the residues implicated in the stabilisation of the lipocalin fold were determined. This was done by analyzing the conserved interactions for ten lipocalins having a maximum pairwise identity of 28% and various functions. RESULTS: It was determined that two hydrophobic clusters of residues are conserved by analysing the ten lipocalin structures and sequences. One cluster is internal to the barrel, involving all strands and the 310 helix. The other is external, involving four strands and the helix lying parallel to the barrel surface. These clusters are also present in RaHBP2, a unusual "outlier" lipocalin from tick Rhipicephalus appendiculatus. This information was used to assess assignment of LIR2 a protein from Ixodes ricinus and to build a 3D model that helps to predict function. FTIR data support the lipocalin fold for this protein. CONCLUSION: By sequence and structural analyzes, two conserved clusters of hydrophobic residues in interactions have been identified in lipocalins. Since the residues implicated are not conserved for function, they should provide the minimal subset necessary to confer the lipocalin fold. This information has been used to assign LIR2 to lipocalins and to investigate its structure/function relationship. This study could be applied to other protein families with low pairwise similarity, such as the structurally related fatty acid binding proteins or avidins. [less ▲]

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See detailInteractions Of Ciprofloxacin With Dppc And Dppg: Fluorescence Anisotropy, Atr-Ftir And P-31 Nmr Spectroscopies And Conformational Analysis
Bensikaddour, H.; Snoussi, K.; Lins, Laurence ULg et al

in Biochimica et Biophysica Acta-Biomembranes (2008), 1778(11), 2535-43

The interactions between a drug and lipids may be critical for the pharmacological activity. We previously showed that the ability of a fluoroquinolone antibiotic, ciprofloxacin, to induce disorder and ... [more ▼]

The interactions between a drug and lipids may be critical for the pharmacological activity. We previously showed that the ability of a fluoroquinolone antibiotic, ciprofloxacin, to induce disorder and modify the orientation of the acyl chains is related to its propensity to be expelled from a monolayer upon compression [1]. Here, we compared the binding of ciprofloxacin on DPPC and DPPG liposomes (or mixtures of phospholipids [DOPC:DPPC], and [DOPC:DPPG]) using quasi-elastic light scattering and steady-state fluorescence anisotropy. We also investigated ciprofloxacin effects on the transition temperature (T(m)) of lipids and on the mobility of phosphate head groups using Attenuated Total Reflection Fourier Transform Infrared-Red Spectroscopy (ATR-FTIR) and (31)P Nuclear Magnetic Resonance (NMR) respectively. In the presence of ciprofloxacin we observed a dose-dependent increase of the size of the DPPG liposomes whereas no effect was evidenced for DPPC liposomes. The binding constants K(app) were in the order of 10(5) M(-1) and the affinity appeared dependent on the negative charge of liposomes: DPPG>DOPC:DPPG (1:1; M:M)>DPPC>DOPC:DPPC (1:1; M:M). As compared to the control samples, the chemical shift anisotropy (Deltasigma) values determined by (31)P NMR showed an increase of 5 and 9 ppm for DPPC:CIP (1:1; M:M) and DPPG:CIP (1:1; M:M) respectively. ATR-FTIR experiments showed that ciprofloxacin had no effect on the T(m) of DPPC but increased the order of the acyl chains both below and above this temperature. In contrast, with DPPG, ciprofloxacin induced a marked broadening effect on the transition with a decrease of the acyl chain order below its T(m) and an increase above this temperature. Altogether with the results from the conformational analysis, these data demonstrated that the interactions of ciprofloxacin with lipids depend markedly on the nature of their phosphate head groups and that ciprofloxacin interacts preferentially with anionic lipid compounds, like phosphatidylglycerol, present at a high content in these membranes. [less ▲]

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See detailIr-LBP, an ixodes ricinus tick salivary LTB4-binding lipocalin, interferes with host neutrophil function.
Beaufays, Jérôme ULg; Adam, Benoit; Menten-Dedoyart, Catherine ULg et al

in PLoS ONE (2008), 3(12), 3987

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 ... [more ▼]

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. [less ▲]

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See detailTilted peptides: a structural motif involved in protein membrane insertion?
Lins, Laurence ULg; Brasseur, Robert ULg

in Journal of Peptide Science : An Official Publication of the European Peptide Society (2008), 14(4), 416-22

Tilted peptides are short hydrophobic protein fragments characterized by an asymmetric distribution of their hydrophobic residues when helical. They are able to interact with a hydrophobic/hydrophilic ... [more ▼]

Tilted peptides are short hydrophobic protein fragments characterized by an asymmetric distribution of their hydrophobic residues when helical. They are able to interact with a hydrophobic/hydrophilic interface (such as a lipid membrane) and to destabilize the organized system into which they insert. They were detected in viral fusion proteins and in proteins involved in different biological processes involving membrane insertion or translocation of the protein in which they are found. In this paper, we have analysed different protein domains related to membrane insertion with regard to their tilted properties. They are the N-terminal signal peptide of the filamentous haemagglutinin (FHA), a Bordetella pertussis protein secreted in high amount and the hydrophobic domain from proteins forming pores (i.e. ColIa, Bax and Bcl-2). From the predictions and the experimental approaches, we suggest that tilted peptides found in those proteins could have a more general role in the mechanism of insertion/translocation of proteins into/across membranes. For the signal sequences, they could help the protein machinery involved in protein secretion to be more active. In the case of toroidal pore formation, they could disturb the lipids, facilitating the insertion of the other more hydrophilic helices. [less ▲]

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See detailCharacterization of the interactions between fluoroquinolone antibiotics and lipids: a multitechnique approach.
Bensikaddour, Hayet; Fa, Nathalie; Burton, Ingrid et al

in Biophysical Journal (2008), 94(8), 3035-46

Probing drug/lipid interactions at the molecular level represents an important challenge in pharmaceutical research and membrane biophysics. Previous studies showed differences in accumulation and ... [more ▼]

Probing drug/lipid interactions at the molecular level represents an important challenge in pharmaceutical research and membrane biophysics. Previous studies showed differences in accumulation and intracellular activity between two fluoroquinolones, ciprofloxacin and moxifloxacin, that may actually result from their differential susceptibility to efflux by the ciprofloxacin transporter. In view of the critical role of lipids for the drug cellular uptake and differences observed for the two closely related fluoroquinolones, we investigated the interactions of these two antibiotics with lipids, using an array of complementary techniques. Moxifloxacin induced, to a greater extent than ciprofloxacin, an erosion of the DPPC domains in the DOPC fluid phase (atomic force microscopy) and a shift of the surface pressure-area isotherms of DOPC/DPPC/fluoroquinolone monolayer toward lower area per molecule (Langmuir studies). These effects are related to a lower propensity of moxifloxacin to be released from lipid to aqueous phase (determined by phase transfer studies and conformational analysis) and a marked decrease of all-trans conformation of acyl-lipid chains of DPPC (determined by ATR-FTIR) without increase of lipid disorder and change in the tilt between the normal and the germanium surface (also determined by ATR-FTIR). All together, differences of ciprofloxacin as compared to moxifloxacin in their interactions with lipids could explain differences in their cellular accumulation and susceptibility to efflux transporters. [less ▲]

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See detailEffects Of Six Apoa5 Variants, Identified In Patients With Severe Hypertriglyceridemia, On In Vitro Lipoprotein Lipase Activity And Receptor Binding
Dorfmeister, B.; Zeng, Ww.; Dichlberger, A. et al

in Arteriosclerosis, Thrombosis, and Vascular Biology (2008), 28(10), 1866-71

OBJECTIVE: The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible ... [more ▼]

OBJECTIVE: The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible. METHODS AND RESULTS: We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -Delta139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (-25% [P=0.005], -36% [P<0.0001], and -23% [P=0.02]), respectively). ApoAV-C271, -X139, -X148, and Delta139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant. CONCLUSIONS: The in vitro determined function of these apoAV variants only partly explains the high TG levels seen in carriers. Their occurrence in the homozygous state, coinheritance of LPL variants or common APOA5 TG-raising variant in trans, appears to be essential for their phenotypic expression. [less ▲]

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