Biochimica et biophysica acta. Biomembranes最新文献

{"title":"Probing phosphorylation events in biological membranes: The transducer function","authors":"Daniel Wirth,&nbsp;Ece Özdemir,&nbsp;Kalina Hristova","doi":"10.1016/j.bbamem.2024.184362","DOIUrl":"10.1016/j.bbamem.2024.184362","url":null,"abstract":"<div><p>The extracellular environment is sensed by receptors in the plasma membrane. Some of these receptors initiate cytoplasmic signaling cascades involving phosphorylation: the addition of a phosphate group to a specific amino acid, such as tyrosine, in a protein. Receptor Tyrosine Kinases (RTKs) are one large class of membrane receptors that can directly initiate signaling cascades through their intracellular kinase domains, which both catalyze tyrosine phosphorylation and get phosphorylated. In the first step of signaling, the ligands stabilize phosphorylation-competent RTK dimers and oligomers, which leads to the phosphorylation of specific tyrosine residues in the activation loop of the kinases. Here we discuss quantitative measurements of tyrosine phosphorylation efficiencies for RTKs, described by the “transducer function”. The transducer function links the phosphorylation (the response) and the binding of the activating ligand to the receptor (the stimulus). We overview a methodology that allows such measurements in direct response to ligand binding. We discuss experiments which demonstrate that EGF is a partial agonist, and that two tyrosines in the intracellular domain of EGFR, Y1068 and Y1173, are differentially phosphorylated in the EGF-bound EGFR dimers.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 7","pages":"Article 184362"},"PeriodicalIF":3.4,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141413247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of amino acids in transmembrane domains of mutated cytokine receptor-like factor 2 and interleukin-7 receptor α required for constitutive signal transduction","authors":"Rio Yamamoto ,&nbsp;Ryosuke Segawa ,&nbsp;Hiyori Kato ,&nbsp;Yuya Niino ,&nbsp;Takeshi Sato ,&nbsp;Masahiro Hiratsuka ,&nbsp;Noriyasu Hirasawa","doi":"10.1016/j.bbamem.2024.184359","DOIUrl":"10.1016/j.bbamem.2024.184359","url":null,"abstract":"<div><p>Cytokine receptor-like factor 2 (CRLF2) and interleukin-7 receptor α (IL-7Rα) form a receptor for thymic stromal lymphopoietin (TSLP). A somatic mutation consisting of the substitution of five amino acids (SLLLL) in the transmembrane domain of CRLF2 with three amino acids, including glutamic acid, isoleucine, and methionine (insEIM), which has been identified in acute lymphocytic leukemia, causes the TSLP-independent dimerization with IL-7Rα and activation. However, the dimerization mechanism remains unclear. In this study, we examined the involvement of the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα in TSLP-independent activation. HEK293 cells were transfected with vectors encoding CRLF2 and IL-7Rα, or their mutants, in which the amino acid of the transmembrane domain was replaced with alanine. STAT5 phosphorylation was detected using western blotting, and receptor dimerization was analyzed using the NanoBiT assay. The substitution of glutamic acid within the insEIM mutation for alanine failed to cause the STAT5 phosphorylation in the absence of TSLP. Moreover, the alanine substation of the specific leucine residues in the transmembrane domains of both CRLF2 and IL-7Rα abrogated the TSLP-independent signal transduction and dimerization. The mutation of IL-7Rα W264 partially reduced the phosphorylation of STAT5 without affecting receptor dimerization. These results suggest that the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα play at least three possible functions: interaction through hydrogen bonds, hydrophobic interaction, and signal transduction. Our findings contribute to a better understanding of the function of the transmembrane domains of cytokine receptors in their dimerization and signal transduction.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 7","pages":"Article 184359"},"PeriodicalIF":3.4,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0005273624000907/pdfft?md5=c5faeded3928ce08736ddb80ef74b200&pid=1-s2.0-S0005273624000907-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutron spin echo shows pHLIP is capable of retarding membrane thickness fluctuations","authors":"Haden L. Scott ,&nbsp;Violeta Burns-Casamayor ,&nbsp;Andrew C. Dixson ,&nbsp;Robert F. Standaert ,&nbsp;Christopher B. Stanley ,&nbsp;Laura-Roxana Stingaciu ,&nbsp;Jan-Michael Y. Carrillo ,&nbsp;Bobby G. Sumpter ,&nbsp;John Katsaras ,&nbsp;Wei Qiang ,&nbsp;Frederick A. Heberle ,&nbsp;Blake Mertz ,&nbsp;Rana Ashkar ,&nbsp;Francisco N. Barrera","doi":"10.1016/j.bbamem.2024.184349","DOIUrl":"10.1016/j.bbamem.2024.184349","url":null,"abstract":"<div><p>Cell membranes are responsible for a range of biological processes that require interactions between lipids and proteins. While the effects of lipids on proteins are becoming better understood, our knowledge of how protein conformational changes influence membrane dynamics remains rudimentary. Here, we performed experiments and computer simulations to study the dynamic response of a lipid membrane to changes in the conformational state of pH-low insertion peptide (pHLIP), which transitions from a surface-associated (SA) state at neutral or basic pH to a transmembrane (TM) α-helix under acidic conditions. Our results show that TM-pHLIP significantly slows down membrane thickness fluctuations due to an increase in effective membrane viscosity. Our findings suggest a possible membrane regulatory mechanism, where the TM helix affects lipid chain conformations, and subsequently alters membrane fluctuations and viscosity.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 7","pages":"Article 184349"},"PeriodicalIF":3.4,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ergosterol promotes aggregation of natamycin in the yeast plasma membrane","authors":"Maria Szomek ,&nbsp;Vibeke Akkerman ,&nbsp;Line Lauritsen ,&nbsp;Hanna-Loisa Walther ,&nbsp;Alice Dupont Juhl ,&nbsp;Katja Thaysen ,&nbsp;Jacob Marcus Egebjerg ,&nbsp;Douglas F. Covey ,&nbsp;Max Lehmann ,&nbsp;Pablo Wessig ,&nbsp;Alexander J. Foster ,&nbsp;Bert Poolman ,&nbsp;Stephan Werner ,&nbsp;Gerd Schneider ,&nbsp;Peter Müller ,&nbsp;Daniel Wüstner","doi":"10.1016/j.bbamem.2024.184350","DOIUrl":"10.1016/j.bbamem.2024.184350","url":null,"abstract":"<div><p>Polyene macrolides are antifungal substances, which interact with cells in a sterol-dependent manner. While being widely used, their mode of action is poorly understood. Here, we employ ultraviolet-sensitive (UV) microscopy to show that the antifungal polyene natamycin binds to the yeast plasma membrane (PM) and causes permeation of propidium iodide into cells. Right before membrane permeability became compromised, we observed clustering of natamycin in the PM that was independent of PM protein domains. Aggregation of natamycin was paralleled by cell deformation and membrane blebbing as revealed by soft X-ray microscopy. Substituting ergosterol for cholesterol decreased natamycin binding and caused a reduced clustering of natamycin in the PM. Blocking of ergosterol synthesis necessitates sterol import via the ABC transporters Aus1/Pdr11 to ensure natamycin binding. Quantitative imaging of dehydroergosterol (DHE) and cholestatrienol (CTL), two analogues of ergosterol and cholesterol, respectively, revealed a largely homogeneous lateral sterol distribution in the PM, ruling out that natamycin binds to pre-assembled sterol domains. Depletion of sphingolipids using myriocin increased natamycin binding to yeast cells, likely by increasing the ergosterol fraction in the outer PM leaflet. Importantly, binding and membrane aggregation of natamycin was paralleled by a decrease of the dipole potential in the PM, and this effect was enhanced in the presence of myriocin. We conclude that ergosterol promotes binding and aggregation of natamycin in the yeast PM, which can be synergistically enhanced by inhibitors of sphingolipid synthesis.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 7","pages":"Article 184350"},"PeriodicalIF":3.4,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Divalent cations promote huntingtin fibril formation on endoplasmic reticulum derived and model membranes","authors":"Adam Skeens ,&nbsp;Jordyn M. Markle ,&nbsp;Gabriella Petipas ,&nbsp;Shelli L. Frey ,&nbsp;Justin Legleiter","doi":"10.1016/j.bbamem.2024.184339","DOIUrl":"10.1016/j.bbamem.2024.184339","url":null,"abstract":"<div><p>Huntington's Disease (HD) is caused by an abnormal expansion of the polyglutamine (polyQ) domain within the first exon of the huntingtin protein (htt). This expansion promotes disease-related htt aggregation into amyloid fibrils and the formation of proteinaceous inclusion bodies within neurons. Fibril formation is a complex heterogenous process involving an array of aggregate species such as oligomers, protofibrils, and fibrils. In HD, structural abnormalities of membranes of several organelles develop. In particular, the accumulation of htt fibrils near the endoplasmic reticulum (ER) impinges upon the membrane, resulting in ER damage, altered dynamics, and leakage of Ca²⁺. Here, the aggregation of htt at a bilayer interface assembled from ER-derived liposomes was investigated, and fibril formation directly on these membranes was enhanced. Based on these observations, simplified model systems were used to investigate mechanisms associated with htt aggregation on ER membranes. As the ER-derived liposome fractions contained residual Ca²⁺_, the role of divalent cations was also investigated. In the absence of lipids, divalent cations had minimal impact on htt structure and aggregation. However, the presence of Ca²⁺ or Mg²⁺ played a key role in promoting fibril formation on lipid membranes despite reduced htt insertion into and association with lipid interfaces, suggesting that the ability of divalent cations to promote fibril formation on membranes is mediated by induced changes to the lipid membrane physicochemical properties. With enhanced concentrations of intracellular calcium being a hallmark of HD, the ability of divalent cations to influence htt aggregation at lipid membranes may play a role in aggregation events that lead to organelle abnormalities associated with disease.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 6","pages":"Article 184339"},"PeriodicalIF":3.4,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Different lateral packing stress in acyl chains alters KcsA orientation and structure in lipid membranes","authors":"Eri Saki H. Hayakawa ,&nbsp;Misuzu Ueki ,&nbsp;Elmukhtar Alhatmi ,&nbsp;Shigetoshi Oiki ,&nbsp;Fuyuki Tokumasu ,&nbsp;Drake C. Mitchell ,&nbsp;Masayuki Iwamoto","doi":"10.1016/j.bbamem.2024.184338","DOIUrl":"10.1016/j.bbamem.2024.184338","url":null,"abstract":"<div><p>The molecular structures of the various intrinsic lipids in membranes regulate lipid-protein interactions. These different lipid structures with unique volumes produce different lipid molecular packing stresses/lateral stresses in lipid membranes. Most studies examining lipid packing effects have used phosphatidylcholine and phosphatidylethanolamine (PE), which are the main phospholipids of eukaryotic cell membranes. In contrast, Gram-negative or Gram-positive bacterial membranes are composed primarily of phosphatidylglycerol (PG) and PE, and the physical and thermodynamic properties of each acyl chain in PG at the molecular level remain unresolved. In this study, we used 1-palmitoyl-2-oleoyl-<em>sn</em>-glycero-3-phospho-(1′-rac-glycerol) (POPG, 16:0–18:1 PG) and 1-palmitoyl-2-arachidonoyl-<em>sn</em>-glycero-3-phospho-(1′-rac-glycerol) (PAPG, 16:0–20:4 PG) to prepare lipid bilayers (liposome) with the rod-type fluorescence probe DPH. We measured the lipid packing conditions by determining the rotational freedom of DPH in POPG or PAPG bilayers. Furthermore, we investigated the effect of different monoacyl chains on a K⁺ channel (KcsA) structure when embedded in POPG or PAPG membranes. The results revealed that differences in the number of double bonds and carbon chain length in the monoacyl chain at <em>sn</em>-2 affected the physicochemical properties of the membrane and the structure and orientation of KcsA.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 6","pages":"Article 184338"},"PeriodicalIF":3.4,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flow-based bioconjugation of coumarin phosphatidylethanolamine probes: Optimised synthesis and membrane molecular dynamics studies","authors":"Pedro A.M.M. Varandas ,&nbsp;Ricardo Belinha ,&nbsp;Alexander J.A. Cobb ,&nbsp;João P. Prates Ramalho ,&nbsp;Marcela A. Segundo ,&nbsp;Luís M.S. Loura ,&nbsp;Eduarda M.P. Silva","doi":"10.1016/j.bbamem.2024.184335","DOIUrl":"10.1016/j.bbamem.2024.184335","url":null,"abstract":"<div><p>A series of phosphatidylethanolamine fluorescent probes head-labelled with 3-carboxycoumarin was prepared by an improved bioconjugation approach through continuous flow synthesis. The established procedure, supported by a design of experiment (DoE) set-up, resulted in a significant reduction in the reaction time compared to the conventional batch method, in addition to a minor yield increase. The characterization of these probes was enhanced by an in-depth molecular dynamics (MD) study of the behaviour of a representative probe of this family, 1-palmitoyl-2-oleoyl-<em>sn</em>-glycero-3-phosphoethanolamine labelled with 3-carboxycoumarin (POPE-COUM), in bilayers of 1-palmitoyl-2-oleoyl-<em>sn</em>-glycero-3-phosphocholine (POPC)/1-stearoyl-2-linoleoyl-<em>sn</em>-glycero-3-phosphocholine (SLPC) 2:1, mimicking the composition of the egg yolk lecithin membranes recently used experimentally by our group to study POPE-COUM as a biomarker of the oxidation state and integrity of large unilamellar vesicles (LUVs). The MD simulations revealed that the coumarin group is oriented towards the bilayer interior, leading to a relatively internal location, in agreement with what is observed in the nitrobenzoxadiazole fluorophore of commercial head-labelled NBD-PE probes. This behaviour is consistent with the previously stated hypothesis that POPE-COUM is entirely located within the LUVs structure. Hence, the delay on the oxidation of the probe in the oxygen radical absorbance capacity (ORAC) assays performed is related with the inaccessibility of the probe until alteration of the LUV structure occurs. Furthermore, our simulations show that POPE-COUM exerts very little global and local perturbation on the host bilayer, as evaluated by key properties of the unlabelled lipids. Together, our findings establish PE-COUM as suitable fluorescent lipid analogue probes.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 7","pages":"Article 184335"},"PeriodicalIF":3.4,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S000527362400066X/pdfft?md5=07714a0a3090784aa4fc7033fdd2c942&pid=1-s2.0-S000527362400066X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of protease resistant and non-cytotoxic Jelleine analogs with enhanced broad spectrum antimicrobial efficacy","authors":"Tanumoy Sarkar ,&nbsp;S.R. Vignesh ,&nbsp;Tanya Sehgal ,&nbsp;K.R. Ronima ,&nbsp;Rajkumar P. Thummer ,&nbsp;Priyadarshi Satpati ,&nbsp;Sunanda Chatterjee","doi":"10.1016/j.bbamem.2024.184336","DOIUrl":"10.1016/j.bbamem.2024.184336","url":null,"abstract":"<div><p>Short systemic half- life of Antimicrobial Peptides (AMP) is one of the major bottlenecks that limits their successful commercialization as therapeutics. In this work, we have designed analogs of the natural AMP Jelleine, obtained from royal jelly of <em>apis mellifera</em>. Among the designed peptides, <strong>J3</strong> and <strong>J4</strong> were the most potent with broad spectrum activities against a varied class of ESKAPE pathogens and fungus <em>C. albicans</em>. All the developed peptides were more effective against Gram-negative bacteria in comparison to the Gram-positive pathogens, and were especially effective against <em>P. aeruginosa</em> and <em>C. albicans.</em> <strong>J3</strong> and <strong>J4</strong> were completely trypsin resistant and serum stable, while retaining the non-cytotoxicity of the parent Jelleine, <strong>Jc</strong>. The designed peptides were membranolytic in their mode of action. CD and MD simulations in the presence of bilayers, established that <strong>J3</strong> and <strong>J4</strong> were non-structured even upon membrane binding and suggested that biological properties of the AMPs were innocent of any specific secondary structural requirements. Enhancement of charge to increase the antimicrobial potency, controlling the hydrophobic-hydrophilic balance to maintain non-cytotoxicity and induction of unnatural amino acid residues to impart protease resistance, remains some of the fundamental principles in the design of more effective antimicrobial therapeutics of the future, which may help combat the quickly rising menace of antimicrobial resistance in the microbes.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 6","pages":"Article 184336"},"PeriodicalIF":3.4,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141039424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G protein β subunits regulate Cav3.3 T-type channel activity and current kinetics via interaction with the Cav3.3 C-terminus","authors":"Sua Jeong ,&nbsp;Bo-Young Lee ,&nbsp;Jeong Seop Rhee ,&nbsp;Jung-Ha Lee","doi":"10.1016/j.bbamem.2024.184337","DOIUrl":"10.1016/j.bbamem.2024.184337","url":null,"abstract":"<div><p>Ca²⁺ influx through Ca_v3.3 T-type channel plays crucial roles in neuronal excitability and is subject to regulation by various signaling molecules. However, our understanding of the partners of Ca_v3.3 and the related regulatory pathways remains largely limited. To address this quest, we employed the rat Ca_v3.3 C-terminus as bait in yeast-two-hybrid screenings of a cDNA library, identifying rat Gβ₂ as an interaction partner. Subsequent assays revealed that the interaction of Gβ₂ subunit was specific to the Ca_v3.3 C-terminus. Through systematic dissection of the C-terminus, we pinpointed a 22 amino acid sequence (amino acids 1789–1810) as the Gβ₂ interaction site. Coexpression studies of rat Ca_v3.3 with various Gβγ compositions were conducted in HEK-293 cells. Patch clamp recordings revealed that coexpression of Gβ₂γ₂ reduced Ca_v3.3 current density and accelerated inactivation kinetics. Interestingly, the effects were not unique to Gβ₂γ_2, but were mimicked by Gβ₂ alone as well as other Gβγ dimers, with similar potencies. Deletion of the Gβ₂ interaction site abolished the effects of Gβ₂γ₂. Importantly, these Gβ₂ effects were reproduced in human Ca_v3.3. Overall, our findings provide evidence that Gβ(γ) complexes inhibit Ca_v3.3 channel activity and accelerate the inactivation kinetics through the Gβ interaction with the Ca_v3.3 C-terminus.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 6","pages":"Article 184337"},"PeriodicalIF":3.4,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141028948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol drives enantiospecific effects of ibuprofen in biomimetic membranes","authors":"Alexa Guglielmelli ,&nbsp;Caterina M. Tone ,&nbsp;Eleonora Ragozzino ,&nbsp;Federica Ciuchi ,&nbsp;Rosa Bartucci","doi":"10.1016/j.bbamem.2024.184334","DOIUrl":"10.1016/j.bbamem.2024.184334","url":null,"abstract":"<div><p>The interaction between chiral drugs and biomimetic membranes is of interest in biophysical research and biotechnological applications. There is a belief that the membrane composition, particularly the presence of cholesterol, could play a pivotal role in determining enantiospecific effects of pharmaceuticals. Our study explores this topic focusing on the interaction of ibuprofen enantiomers (S- and R-IBP) with cholesterol-containing model membranes. The effects of S- and R-IBP at 20 mol% on bilayer mixtures of dipalmitoylphosphatidylcholine (DPPC) with 0, 10, 20 and 50 mol% cholesterol were investigated using circular dichroism and spin-label electron spin resonance. Morphological changes due to IBP enantiomers were studied with atomic force microscopy on supported cholesterol-containing DPPC monolayers. The results reveal that IBP isoforms significantly and equally interact with pure DPPC lipid assemblies. Cholesterol content, besides modifying the structure and the morphology of the membranes, triggers the drug enantioselectivity at 10 and 20 mol%, with the enantiomers differently adsorbing on membranes and perturbing them. The spectroscopic and the microscopic data indicate that IBP stereospecificity is markedly reduced at equimolar content of Chol mixed with DPPC. This study provides new insights into the role of cholesterol in modulating enantiospecific effects of IBP in lipid membranes.</p></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1866 5","pages":"Article 184334"},"PeriodicalIF":3.4,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0005273624000658/pdfft?md5=331cc2e8f80638d37642e05ad0b8f544&pid=1-s2.0-S0005273624000658-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}