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| Open AccessMechanism of action for small-molecule inhibitors of triacylglycerol synthesis
Sui et al. elucidate the mechanisms of action for small molecule inhibitors of human triacylglycerol synthesis enzyme DGAT1 and provide insights into how these inhibitors achieve selectivity for DGAT1 rather than other closely related MBOAT enzymes.
- Xuewu Sui
- , Kun Wang
- & Tobias C. Walther
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Article
| Open AccessDe novo cholesterol biosynthesis in bacteria
Production of highly modified sterols, such as cholesterol, is essential to eukaryotic physiology but has not been yet reported for bacteria. Here, Lee et al. show that a marine myxobacterium produces cholesterol, and provide evidence for further downstream modifications in this and other bacterial species.
- Alysha K. Lee
- , Jeremy H. Wei
- & Paula V. Welander
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| Open AccessStructural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex
Whether anionic phospholipids required for respiratory supercomplex (SC) formation is unclear. Here authors resolve SCs from a wild type and cardiolipin-deficient yeast strain at 3.2- 3.3 Å resolution to show that cardiolipin can be replaced by phosphatidylglycerol.
- Corey F. Hryc
- , Venkata K. P. S. Mallampalli
- & William Dowhan
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Article
| Open AccessStructure of a eukaryotic cholinephosphotransferase-1 reveals mechanisms of substrate recognition and catalysis
CDP-alcohol phosphatidyltransferase (CDP-AP) is a family of membrane-embedded enzymes that synthesize phospholipids. The authors report structural and functional studies of a eukaryotic CDP-AP and reveal a catalytic center and structural fold different from these of prokaryotic homologs.
- Lie Wang
- & Ming Zhou
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Article
| Open AccessStructural basis for catalysis of human choline/ethanolamine phosphotransferase 1
Choline/ethanolamine phosphotransferase 1 (CEPT1) catalyzes the last step of the biosynthesis of PC and PE. Here, the authors present the cryo-EM structures of human CEPT1 and its complex with CDP-choline and reveal a hydrophobic chamber to accommodate the acyl tails during the catalytic process.
- Zhenhua Wang
- , Meng Yang
- & Hongwu Qian
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| Open AccessSiglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket
Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer. Here, the authors combine a variety of chemical biology techniques to demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.
- Edward N. Schmidt
- , Dimitra Lamprinaki
- & Matthew S. Macauley
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Article
| Open AccessEther phospholipids are required for mitochondrial reactive oxygen species homeostasis
Cancer cells can be dependent on mitochondrial respiration to survive. Here, in pancreatic cancer cells, the authors show that monounsaturated fatty acids-linked ether lipids maintain mitochondrial redox homeostasis and modulate sensitivity to inhibition to electron transport chain complex I.
- Ziheng Chen
- , I-Lin Ho
- & Haoqiang Ying
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Article
| Open AccessA holistic view on the role of egg yolk in Old Masters’ oil paints
Old Masters used paints containing mixtures of oils and proteins, but we lack an understanding on how and why proteins were used. Here, the authors use egg yolk in combination with two pigments to evaluate how different repartition of proteinaceous binder can be used to control the flow behaviour as well as drying kinetics and chemistry of oil paints.
- Ophélie Ranquet
- , Celia Duce
- & Norbert Willenbacher
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Article
| Open AccessHigh-resolution separation of bioisomers using ion cloud profiling
Ion mobility is used in mass spectrometers for structure analysis of biomolecules. Here, the authors show that ion mobility analysis in an ion trap under ultra-high fields enables isomer separation at resolutions over 10,000, wich they demonstrate for isomers of disaccharides, phospholipids, and peptides.
- Xiaoyu Zhou
- , Zhuofan Wang
- & Zheng Ouyang
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Article
| Open AccessInsights into membrane association of the SMP domain of extended synaptotagmin
The SMP domain of E-Syts is a newly identified lipid transfer module with unclear mechanisms. Here, authors show that it uses its tip region to associate with the extremely curved or negatively charged membranes to extract and unload lipids.
- Yunyun Wang
- , Zhenni Li
- & Xin Bian
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Article
| Open AccessDe novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics
The function of de novo lipogenesis (DNL) in adipocytes has been a mystery as it contributes little to fat storage in these cells. Here, the authors show that DNL is a critical source of fatty acids for membrane-expanding processes like autophagy.
- Leslie A. Rowland
- , Adilson Guilherme
- & Michael P. Czech
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Article
| Open AccessSsu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation
Brown adipose tissue (BAT) is a specialized thermogenic organ that undergoes high demands of protein synthesis during thermogenic adaptation. Here, the authors show that the cold responsive phosphatase Ssu72 is required for mRNA translation that affects thermogenic adaptation in BAT.
- Eun-Ji Park
- , Hyun-Soo Kim
- & Chang-Woo Lee
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Article
| Open AccessCholesterol esters form supercooled lipid droplets whose nucleation is facilitated by triacylglycerols
Dumesnil et al. report that cholesterol esters (CE), which only melt above body temperature, form supercooled liquid crystalline lipid droplets (LD). Triacylglycerols (TG) solubilize CE to help CE LD nucleation. Through clustering TGs in the ER membrane, seipin controls CE LD nucleation sites.
- Calvin Dumesnil
- , Lauri Vanharanta
- & Abdou Rachid Thiam
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Article
| Open AccessRetinoids stored locally in the lung are required to attenuate the severity of acute lung injury in male mice
Retinoids can act as transcriptional regulators to regulate cell proliferation, differentiation, and other processes. Here, the authors show that uncompromised vitamin A (retinoid) metabolism and signaling in alveolar lipofibroblasts, endothelial and epithelial cells are required to lessen the severity of an acute inflammatory challenge in adult mouse lungs.
- Igor O. Shmarakov
- , Galina A. Gusarova
- & William S. Blaner
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Article
| Open AccessLipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats
How the liver mitochondria seamlessly regulate lipogenesis and lipid oxidation is unknown. Here, the authors report two functionally distinct populations of mitochondria, cytoplasmic and lipid droplet-associated mitochondria, and demonstrate that the latter’s lipid oxidation function is impaired in a rat NAFLD model.
- Noble Kumar Talari
- , Ushodaya Mattam
- & Naresh Babu V. Sepuri
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| Open AccessThe p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition
Inter-organellar contacts are hubs for several critical cellular processes, such as lipid synthesis. Here Ganji et al. show that the p97-UBXD8 complex modulates contacts by regulating membrane lipid composition and saturation.
- Rakesh Ganji
- , Joao A. Paulo
- & Malavika Raman
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Article
| Open AccessAn engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration
Mitochondrial fatty acid synthesis (mtFAS) generates the precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. Here, the authors generated an engineered variant of human 2E-enoyl-ACP reductase (MECR) of mtFAS to study the role of long chain fatty acids.
- M. Tanvir Rahman
- , M. Kristian Koski
- & Kaija J. Autio
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| Open AccessLipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response
Circulating lipids can influence immune cell function, which could have implications for inflammatory diseases such as rheumatoid arthritis. Here, the authors use Mendelian randomization to identify genes whose expression is influenced by triglyceride levels in blood, implicating genes involved in lipid metabolism and allergic response.
- Koen F. Dekkers
- , Roderick C. Slieker
- & Bastiaan T. Heijmans
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| Open AccessGlycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
KRAS is a small GTPase that regulates cell proliferation. Here, the authors show that a subset of cell surface glycosphingolipids regulate KRAS plasma membrane localization by modulating inner leaflet lipid composition, uncovering a requirement for KRAS oncogenesis that may have therapeutic potential.
- Junchen Liu
- , Ransome van der Hoeven
- & John F. Hancock
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| Open AccessLong-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice
Huang et al. investigated the effects of long-term statins administration in a mouse model for diabetes and found that it can worsen insulin resistance, renal inflammation and fibrosis. Statins increased renal lipid uptake and inhibited fatty acid oxidation, contributing to diabetic nephropathy.
- Tong-sheng Huang
- , Teng Wu
- & Wei-bin Cai
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Article
| Open AccessThe lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis
Ferroptosis is cell death caused by lipid peroxidation and plasma membrane rupture. Here, the authors report an additional role for the lipid flippase SLC47A1 as a regulator of lipid remodeling and survival during ferroptosis, thereby providing a metabolic target for overcoming drug resistance.
- Zhi Lin
- , Jiao Liu
- & Minghua Yang
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Article
| Open AccessStructural basis for the activation of the lipid scramblase TMEM16F
TMEM16F is a dual ion channel and lipid scramblase that is involved in blood coagulation and cell fusion. Here, authors elucidate how the protein is activated by Ca2+ to accomplish both functions in a single protein conformation.
- Melanie Arndt
- , Carolina Alvadia
- & Raimund Dutzler
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Article
| Open AccessAnalytical and computational workflow for in-depth analysis of oxidized complex lipids in blood plasma
Oxidized lipids are prominent bioactive agents, and yet their molecular repertoire remains largely unknown. Here, the authors apply bioinformatics and LC-MS/MS to uncover the diversity and specificity of modified lipids in human blood plasma of lean and obese individuals.
- Angela Criscuolo
- , Palina Nepachalovich
- & Maria Fedorova
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Article
| Open AccessAntibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane
Manioglu et al use high-resolution atomic force microscopy to resolve how polymyxins interact with the bacterial membrane. Polymyxins arrange the bacterial lipids into regular hexagonal structures that stiffen the membrane and lead to rupture.
- Selen Manioglu
- , Seyed Majed Modaresi
- & Sebastian Hiller
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| Open AccessThe cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics
The functions of specific lipids in autophagosome biogenesis are not entirely clear. Here, the authors show that the ER protein GRAMD1C, a cholesterol transport protein, suppresses autophagy initiation and has roles in mitochondrial cholesterol homeostasis and respiration.
- Matthew Yoke Wui Ng
- , Chara Charsou
- & Anne Simonsen
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Article
| Open AccessTLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis
The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis.
- Kasparas Petkevicius
- , Henrik Palmgren
- & Xiao-Rong Peng
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Article
| Open AccessChronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue
Dietary sugar intake may contribute to the development non-alcoholic fatty liver disease. Here the authors investigated the effects of chronic dietary sucrose on the liver-adipose-microbiome axis in mice, and report that sex is a moderating factor that influences sucrose-driven lipid storage in the liver and adipose tissue lipolysis.
- Erin J. Stephenson
- , Amanda S. Stayton
- & Joan C. Han
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Article
| Open AccessDeficiency of the frontotemporal dementia gene GRN results in gangliosidosis
Progranulin-deficieny results in gangliosidosis due to reduced lysosomal lipids (BMP) required for ganglioside degradation. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD.
- Sebastian Boland
- , Sharan Swarup
- & Robert V. Farese Jr
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Article
| Open AccessNeolithic culinary traditions revealed by cereal, milk and meat lipids in pottery from Scottish crannogs
Despite archaeobotanical evidence for domesticated cereals, organic residue evidence is scarce. Here, the authors identify cereal-specific markers in pottery from Scottish ‘crannogs’, revealing the presence of cereals in Neolithic pottery which might have been mixed with dairy products as a milk-based gruel.
- Simon Hammann
- , Rosie R. Bishop
- & Lucy J. E. Cramp
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| Open AccessMultivalent interactions between molecular components involved in fast endophilin mediated endocytosis drive protein phase separation
Here the authors show that protein phase separation is a key mechanism in cellular receptor internalization via fast endophilin mediated endocytosis (FEME). Phase separation facilitates multivalent FEME-protein assembly in this clathrin-independent pathway.
- Samsuzzoha Mondal
- , Karthik Narayan
- & Tobias Baumgart
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Article
| Open AccessRegulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain
HMG-CoA reductase (HMGCR) is regulated by UBIAD1 and Insigs and initializes cholesterol synthesis. Here authors show that the sterol sensing domain of HMGCR undergoes conformational changes to regulate its degradation via binding its protein modulators.
- Hongwen Chen
- , Xiaofeng Qi
- & Xiaochun Li
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Article
| Open AccessLipolysis regulates major transcriptional programs in brown adipocytes
β-Adrenergic signaling is a core regulator of brown adipocyte function. Here, the authors provide unbiased insight into the transcriptional network controlled by lipolysis in brown adipocytes, showing that lipolysis is required for much of the thermogenic gene program activated by β-adrenergic signals.
- Lasse K. Markussen
- , Elizabeth A. Rondini
- & Susanne Mandrup
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Article
| Open AccessIntestine-enriched apolipoprotein b orthologs are required for stem cell progeny differentiation and regeneration in planarians
Lipid metabolism regulates stem cell states and differentiation. Here, the authors demonstrate a requirement in planarians for Apolipoprotein B-mediated neutral lipid transport from intestinal stores to stem cells and their progeny during differentiation and whole-body regeneration.
- Lily L. Wong
- , Christina G. Bruxvoort
- & David J. Forsthoefel
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Article
| Open AccessStructural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites
The ER-mitochondria contact sites are crucial for exchanging phospholipids. Here, Kim et al. present crystal structures of mitoguardin-2 (MIGA2) which reveal that MIGA2 directly binds phospholipids and transfers them between the ER and mitochondria.
- Hyunwoo Kim
- , Seowhang Lee
- & Changwook Lee
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Article
| Open AccessPI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling
Fatty acid unsaturation by stearoyl-CoA desaturase 1 (SCD1) protects against cellular stress through unclear mechanisms. Here the authors show 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) is an SCD1-derived signaling lipid that regulates stress-adaption, protects against cell death and promotes proliferation.
- Maria Thürmer
- , André Gollowitzer
- & Andreas Koeberle
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Article
| Open AccessFunctional expression of opioid receptors and other human GPCRs in yeast engineered to produce human sterols
The yeast Saccharomyces cerevisiae is powerful for studying human G protein-coupled receptors as they can be coupled to its mating pathway. Here the authors engineer baker’s yeast to produce human sterols and show that vertebrate G protein coupled receptors are more sensitive in this membrane environment.
- Björn D. M. Bean
- , Colleen J. Mulvihill
- & Vincent J. J. Martin
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Article
| Open AccessTMEM16 scramblases thin the membrane to enable lipid scrambling
Lipid scrambling is required for many cellular processes but the lipid-protein interactions that occur during transport are unknown. Using cryoEM and biochemical assays the authors show that membrane thinning is critical for lipid flipping.
- Maria E. Falzone
- , Zhang Feng
- & Alessio Accardi
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Article
| Open AccessStatin therapy inhibits fatty acid synthase via dynamic protein modifications
Statin therapy is associated with numerous cellular effects. Here, the authors show that statin treatment increases post-translational modifications on fatty acid synthase in the active site, revealing communication between the cholesterol and lipid biosynthetic pathways.
- Alec G. Trub
- , Gregory R. Wagner
- & Matthew D. Hirschey
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Article
| Open AccessA negative-solvatochromic fluorescent probe for visualizing intracellular distributions of fatty acid metabolites
Metabolic distribution of fatty acids to organelles is an essential biological process for energy homeostasis. Here the authors report a fluorescent probe that allows multicolour visualisation of the intracellular distribution of exogenous fatty acids, metabolically incorporated as lipid components.
- Keiji Kajiwara
- , Hiroshi Osaki
- & Masayasu Taki
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Article
| Open AccessCNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids
Although lipids are known to affect Hedgehog (Hh) signalling, the underlying mechanisms remain unclear. Here, the authors show that Canopy4 regulates membrane sterol lipid levels, with knockout mouse embryos exhibiting digit number changes and other Hh signalling-related developmental defects.
- Megan Lo
- , Amnon Sharir
- & Ophir D. Klein
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Article
| Open AccessPeptidoglycan biosynthesis is driven by lipid transfer along enzyme-substrate affinity gradients
Bacterial cell wall enzymes and their precursors are critical targets for antibiotic development. Here, the authors investigate several biosynthetic enzymes with their substrates and show that the passage of substrates and products in the pathway is controlled by their relative binding affinities.
- Abraham O. Oluwole
- , Robin A. Corey
- & Carol V. Robinson
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Article
| Open AccessCa2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair
Activation of ESCRT prevents potentially lethal outcomes of minor perturbations in lysosomal integrity. Here authors show that Ca2 + -activated scrambling of sphingomyelin and its cytosolic turnover drives lysosomal repair independently of ESCRT.
- Patrick Niekamp
- , Felix Scharte
- & Joost C. M. Holthuis
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Article
| Open AccessIdentification of a protein responsible for the synthesis of archaeal membrane-spanning GDGT lipids
The cell membranes of many archaea contain characteristic membrane-spanning lipids known as glycerol dibiphytanyl glycerol tetraethers. Here, Zeng et al. identify a protein that participates in a key step of the synthesis of these lipids from diether precursors.
- Zhirui Zeng
- , Huahui Chen
- & Paula V. Welander
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Article
| Open AccessEvidence for a trap-and-flip mechanism in a proton-dependent lipid transporter
LtaA catalyzes glycolipid translocation by a ‘trap-and-flip’ mechanism, pointing to a shared mechanistic model among MFS lipid transporters. Asymmetric lateral openings allow access of the entire lipid substrate to the amphipathic central cavity.
- Elisabeth Lambert
- , Ahmad Reza Mehdipour
- & Camilo Perez
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Article
| Open AccessComparative metabolomics with Metaboseek reveals functions of a conserved fat metabolism pathway in C. elegans
Untargeted mass spectrometry-based metabolomics can reveal new biochemistry, but data analysis is challenging. Here, the authors develop Metaboseek, an open-source software that facilitates metabolite discovery, and apply it to characterize fatty acid alpha-oxidation in C. elegans.
- Maximilian J. Helf
- , Bennett W. Fox
- & Frank C. Schroeder
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Article
| Open AccessGiant sponge grounds of Central Arctic seamounts are associated with extinct seep life
This study reports the discovery of dense sponge gardens across the peaks of permanently ice-covered, extinct volcanic seamounts of the Langseth Ridge and on the remnants of a now extinct seep ecosystem. Using approaches to sample and infer food and energy sources to this ice-covered community, the authors suggest that the sponges use refractory organic matter trapped in the extinct seep community on which they sit.
- T. M. Morganti
- , B. M. Slaby
- & A. Boetius
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Article
| Open AccessDifferential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate
Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P1) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA1) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs.
- Shian Liu
- , Navid Paknejad
- & Xin-Yun Huang
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Article
| Open AccessA method to construct the dynamic landscape of a bio-membrane with experiment and simulation
The authors present a strategy to construct dynamic biomolecular landscapes. Here, they derive a quantitative description of the distribution timescales and amplitudes of reorientational motion of POPC membranes from the combination of NMR relaxation data and frame analysis of MD simulations.
- Albert A. Smith
- , Alexander Vogel
- & Daniel Huster
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Article
| Open AccessA mass spectrometric method for in-depth profiling of phosphoinositide regioisomers and their disease-associated regulation
Different phosphoinositide isomers are involved in a variety of physiological and pathological processes. Here, the authors combine chiral column chromatography and mass spectrometry to measure phosphoinositide regioisomers, revealing their dynamic changes in intra- and extracellular cancer cell milieus.
- Shin Morioka
- , Hiroki Nakanishi
- & Takehiko Sasaki