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Lipid gpcr

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https://www.readbyqxmd.com/read/29689227/how-the-ciliary-membrane-is-organized-inside-out-to-communicate-outside-in
#1
REVIEW
Galo Garcia, David R Raleigh, Jeremy F Reiter
Cilia, organelles that move to execute functions like fertilization and signal to execute functions like photoreception and embryonic patterning, are composed of a core of nine-fold doublet microtubules overlain by a membrane. Distinct types of cilia display distinct membrane morphologies, ranging from simple domed cylinders to the highly ornate invaginations and membrane disks of photoreceptor outer segments. Critical for the ability of cilia to signal, both the protein and the lipid compositions of ciliary membranes are different from those of other cellular membranes...
April 23, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29685028/exploring-gpcr-lipid-interactions-by-molecular-dynamics-simulations-excitements-challenges-and-the-way-forward
#2
Durba Sengupta, Xavier Prasanna, Madhura Mohole, Amitabha Chattopadhyay
G protein-coupled receptors (GPCRs) are seven transmembrane receptors that mediate a large number of cellular responses and are important drug targets. One of the current challenges in GPCR biology is to analyze the molecular signatures of receptor-lipid interactions, and their subsequent effects on GPCR structure, organization and function. Molecular dynamics simulation studies have been successful in predicting molecular determinants of receptor-lipid interactions. In particular, predicted cholesterol interaction sites appear to correspond well with experimentally determined binding sites and estimated time scales of association...
April 23, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29673577/profiling-of-g-protein-coupled-receptors-in-vagal-afferents-reveals-novel-gut-to-brain-sensing-mechanisms
#3
Kristoffer L Egerod, Natalia Petersen, Pascal N Timshel, Jens C Rekling, Yibing Wang, Qinghua Liu, Thue W Schwartz, Laurent Gautron
OBJECTIVES: G protein-coupled receptors (GPCRs) act as transmembrane molecular sensors of neurotransmitters, hormones, nutrients, and metabolites. Because unmyelinated vagal afferents richly innervate the gastrointestinal mucosa, gut-derived molecules may directly modulate the activity of vagal afferents through GPCRs. However, the types of GPCRs expressed in vagal afferents are largely unknown. Here, we determined the expression profile of all GPCRs expressed in vagal afferents of the mouse, with a special emphasis on those innervating the gastrointestinal tract...
April 3, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29667660/a-new-functional-membrane-protein-microarray-based-on-tethered-phospholipid-bilayers
#4
Meriem Chadli, Ofelia Maniti, Christophe Marquette, Bruno Tillier, Sandra Cortès, Agnès Girard-Egrot
A new prototype of a membrane protein biochip is presented in this article. This biochip was created by the combination of novel technologies of peptide-tethered bilayer lipid membrane (pep-tBLM) formation and solid support micropatterning. Pep-tBLMs integrating a membrane protein were obtained in the form of microarrays on a gold chip. The formation of the microspots was visualized in real-time by surface plasmon resonance imaging (SPRi) and the functionality of a GPCR (CXCR4), reinserted locally into microwells, was assessed by ligand binding studies...
April 18, 2018: Analyst
https://www.readbyqxmd.com/read/29660291/the-molecular-mechanism-underlying-ligand-binding-to-the-membrane-embedded-site-of-a-g-protein-coupled-receptor
#5
Xiao-Jing Yuan, Stefano Raniolo, Vittorio Limongelli, Yechun Xu
The crystal structure of P2Y1 receptor (P2Y1R), a class A GPCR, revealed a special extra-helical site for its antagonist, BPTU, which locates in between the membrane and the protein. However, due to the limitation of crystallization experiments, the membrane was mimicked by use of detergents and the information related to the binding of BPTU to the receptor in the membrane environment is rather limited. In the present work, we conducted a total of ~7.5 µs all-atom simulations in explicit solvent using conventional molecular dynamics and multiple enhanced sampling methods, with models of BPTU and a POPC bilayer, both in the absence and presence of P2Y1R...
April 16, 2018: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29617137/physical-origin-of-thermostabilization-by-a-quadruple-mutation-for-the-adenosine-a-2a-receptor-in-the-active-state
#6
Yuta Kajiwara, Satoshi Yasuda, Simon Hikiri, Tomohiko Hayashi, Mitsunori Ikeguchi, Takeshi Murata, Masahiro Kinoshita
The G protein-coupled receptors (GPCRs) form a large, physiologically important family of membrane proteins and are currently most attractive targets for drug discovery. We investigate the physical origin of thermostabilization of the adenosine A2a receptor (A2aR) in the active state, which was experimentally achieved by another research group using the four point mutations: L48A, A54L, T65A, and Q89A. The investigation is performed on the basis of our recently developed physics-based free-energy function (FEF) which has been quite successful for thermodynamics of GPCRs in the inactive state...
April 4, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29576437/enterochromaffin-5-ht-cells-a-major-target-for-glp-1-and-gut-microbial-metabolites
#7
Mari L Lund, Kristoffer L Egerod, Maja S Engelstoft, Oksana Dmytriyeva, Elvar Theodorsson, Bhavik A Patel, Thue W Schwartz
OBJECTIVES: 5-HT storing enterochromaffin (EC) cells are believed to respond to nutrient and gut microbial components, and 5-HT receptor-expressing afferent vagal neurons have been described to be the major sensors of nutrients in the GI-tract. However, the molecular mechanism through which EC cells sense nutrients and gut microbiota is still unclear. METHODS AND RESULTS: TPH1, the 5-HT generating enzyme, and chromogranin A, an acidic protein responsible for secretory granule storage of 5-HT, were highly enriched in FACS-purified EC cells from both small intestine and colon using a 5-HT antibody-based method...
March 10, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29535353/structural-insights-into-positive-and-negative-allosteric-regulation-of-a-g-protein-coupled-receptor-through-protein-lipid-interactions
#8
Agustín Bruzzese, Carles Gil, James A R Dalton, Jesús Giraldo
Lipids are becoming known as essential allosteric modulators of G protein-coupled receptor (GPCRs). However, how they exert their effects on GPCR conformation at the atomic level is still unclear. In light of recent experimental data, we have performed several long-timescale molecular dynamics (MD) simulations, totalling 24 μs, to rigorously map allosteric modulation and conformational changes in the β2 adrenergic receptor (β2AR) that occur as a result of interactions with three different phospholipids. In particular, we identify different sequential mechanisms behind receptor activation and deactivation, respectively, mediated by specific lipid interactions with key receptor regions...
March 13, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29520682/deuteration-and-selective-labeling-of-alanine-methyl-groups-of-%C3%AE-2-adrenergic-receptor-expressed-in-a-baculovirus-insect-cell-expression-system
#9
Yutaka Kofuku, Tomoki Yokomizo, Shunsuke Imai, Yutaro Shiraishi, Mei Natsume, Hiroaki Itoh, Masayuki Inoue, Kunio Nakata, Shunsuke Igarashi, Hideyuki Yamaguchi, Toshimi Mizukoshi, Ei-Ichiro Suzuki, Takumi Ueda, Ichio Shimada
G protein-coupled receptors (GPCRs) exist in equilibrium between multiple conformations, and their populations and exchange rates determine their functions. However, analyses of the conformational dynamics of GPCRs in lipid bilayers are still challenging, because methods for observations of NMR signals of large proteins expressed in a baculovirus-insect cell expression system (BVES) are limited. Here, we report a method to incorporate methyl-13 C1 H3 -labeled alanine with > 45% efficiency in highly deuterated proteins expressed in BVES...
March 8, 2018: Journal of Biomolecular NMR
https://www.readbyqxmd.com/read/29402834/endothelial-gpr124-exaggerates-the-pathogenesis-of-atherosclerosis-by-activating-inflammation
#10
Dong-Mei Gong, Yan-Li Zhang, Dan-Yang Chen, Ling-Juan Hong, Feng Han, Qi-Bing Liu, Jian-Jun Jiang, Ying-Mei Lu
BACKGROUND/AIMS: Endothelial cell dysfunction is the principal pathological process underlying atherosclerotic cardiovascular disease. G protein-coupled receptor 124 (GPR124), an orphan receptor in the adhesion GPCR subfamily, promotes angiogenesis in the brain. In the present study, we explored the role of endothelial GPR124 in the development and progression of atherosclerosis in adult mice. METHODS: Using tetracycline-inducible transgenic systems, we generated mice expressing GPR124 specifically under control of the Tie-2 promoter...
January 25, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29386184/lysophosphatidic-acid-induces-metabolic-reprogramming-in-ovarian-cancer-via-a-pseudohypoxic-response
#11
Ji Hee Ha, Rangasudhagar Radhakrishnan, Muralidharan Jayaraman, Mingda Yan, Jeremy D Ward, Kar-Ming Fung, Katherine M Moxley, Anil K Sood, Ciro Isidoro, Priyabrata Mukherjee, Yong Sang Song, Danny N Dhanasekaran
Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells...
January 31, 2018: Cancer Research
https://www.readbyqxmd.com/read/29335412/phosphorylation-induced-conformation-of-%C3%AE-2-adrenoceptor-related-to-arrestin-recruitment-revealed-by-nmr
#12
Yutaro Shiraishi, Mei Natsume, Yutaka Kofuku, Shunsuke Imai, Kunio Nakata, Toshimi Mizukoshi, Takumi Ueda, Hideo Iwaï, Ichio Shimada
The C-terminal region of G-protein-coupled receptors (GPCRs), stimulated by agonist binding, is phosphorylated by GPCR kinases, and the phosphorylated GPCRs bind to arrestin, leading to the cellular responses. To understand the mechanism underlying the formation of the phosphorylated GPCR-arrestin complex, we performed NMR analyses of the phosphorylated β2 -adrenoceptor (β2 AR) and the phosphorylated β2 AR-β-arrestin 1 complex, in the lipid bilayers of nanodisc. Here we show that the phosphorylated C-terminal region adheres to either the intracellular side of the transmembrane region or lipids, and that the phosphorylation of the C-terminal region allosterically alters the conformation around M2155...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29311713/towards-high-throughput-gpcr-crystallography-in-meso-soaking-of-adenosine-a-2a-receptor-crystals
#13
Prakash Rucktooa, Robert K Y Cheng, Elena Segala, Tian Geng, James C Errey, Giles A Brown, Robert M Cooke, Fiona H Marshall, Andrew S Doré
Here we report an efficient method to generate multiple co-structures of the A2A G protein-coupled receptor (GPCR) with small-molecules from a single preparation of a thermostabilised receptor crystallised in Lipidic Cubic Phase (LCP). Receptor crystallisation is achieved following purification using a low affinity "carrier" ligand (theophylline) and crystals are then soaked in solutions containing the desired (higher affinity) compounds. Complete datasets to high resolution can then be collected from single crystals and seven structures are reported here of which three are novel...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29290486/mechanisms-of-lipid-scrambling-by-the-g-protein-coupled-receptor-opsin
#14
Giulia Morra, Asghar M Razavi, Kalpana Pandey, Harel Weinstein, Anant K Menon, George Khelashvili
Several class-A G protein-coupled receptor (GPCR) proteins act as constitutive phospholipid scramblases catalyzing the transbilayer translocation of >10,000 phospholipids per second when reconstituted into synthetic vesicles. To address the molecular mechanism by which these proteins facilitate rapid lipid scrambling, we carried out large-scale ensemble atomistic molecular dynamics simulations of the opsin GPCR. We report that, in the process of scrambling, lipid head groups traverse a dynamically revealed hydrophilic pathway in the region between transmembrane helices 6 and 7 of the protein while their hydrophobic tails remain in the bilayer environment...
February 6, 2018: Structure
https://www.readbyqxmd.com/read/29212811/altered-expression-of-hepatic-%C3%AE-adrenergic-receptors-in-aging-rats-implications-for-age-related-metabolic-dysfunction-in-liver
#15
Yun Shi, Zhen-Ju Shu, Hanzhou Wang, Jeffrey L Barnes, Chih-Ko Yeh, Paramita M Ghosh, Michael S Katz, Amrita Kamat
Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand binding studies demonstrated that β-AR density increased by >3-fold in hepatocyte membranes from senescent (24 mo old) compared to young adult (7 mo old) rats, and that this phenomenon was blocked by food restriction which is known to retard aging processes in rodents...
December 6, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29211777/alpha-conotoxin-buia-globular-isomer-is-a-competitive-antagonist-for-oleoyl-l-alpha-lysophosphatidic-acid-binding-to-lpar6-a-molecular-dynamics-study
#16
Saima Younis, Sajid Rashid
Lysophosphatidic acid receptor 6 (LPAR6) is a G-protein coupled receptor (GPCR) involved in hair development and cytoskeleton formation in mammals. Its proliferation is implicated in several forms of cancer including liver cancer, squamous cell carcinoma and metastatic prostate cancer. Current study emphasizes the isolation of competitive non-lipid and stable peptide antagonists for Lysophosphatidic acid ligand. A total of 148 conotoxin structures were characterized for their binding abilities against LPAR6...
2017: PloS One
https://www.readbyqxmd.com/read/29209002/the-orientation-and-stability-of-the-gpcr-arrestin-complex-in-a-lipid-bilayer
#17
Dali Wang, Hua Yu, Xiangdong Liu, Jianqiang Liu, Chen Song
G protein-coupled receptors (GPCRs) constitute a large family of membrane proteins that plays a key role in transmembrane signal transduction and draw wide attention since it was discovered. Arrestin is a small family of proteins which can bind to GPCRs, block G protein interactions and redirect signaling to G-protein-independent pathways. The detailed mechanism of how arrestin interacts with GPCR remains elusive. Here, we conducted molecular dynamics simulations with coarse-grained (CG) and all-atom (AA) models to study the complex structure formed by arrestin and rhodopsin, a prototypical GPCR, in a POPC bilayer...
December 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29198881/role-of-arsenic-exposure-in-adipose-tissue-dysfunction-and-its-possible-implication-in-diabetes-pathophysiology
#18
REVIEW
Kaviyarasi Renu, Harishkumar Madhyastha, Radha Madhyastha, Masugi Maruyama, Sankarganesh Arunachlam, Abilash V G
Exposure to arsenic in drinking water can stimulate a diverse number of diseases that originate from impaired lipid metabolism in adipose and glucose metabolism, leading to insulin resistance. Arsenic inhibits differentiation of adipocyte and mediates insulin resistance with diminutive information on arsenicosis on lipid storage and lipolysis. This review focused on different mechanisms and pathways involved in adipogenesis and lipolysis in adipose tissue during arsenic-induced diabetes. Though arsenic is known to cause type2 diabetes through different mechanisms, the role of adipose tissue in causing type2 diabetes is still unclear...
March 1, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29154090/proliferative-and-metastatic-roles-for-phospholipase-d-in-mouse-models-of-cancer
#19
REVIEW
Eric Roth, Michael A Frohman
Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer...
November 14, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28993767/genomic-programming-of-human-neonatal-dendritic-cells-in-congenital-systemic-and-in-vitro-cytomegalovirus-infection-reveal-plastic-and-robust-immune-pathway-biology-responses
#20
Widad Dantoft, Pablo Martínez-Vicente, James Jafali, Lara Pérez-Martínez, Kim Martin, Konstantinos Kotzamanis, Marie Craigon, Manfred Auer, Neil T Young, Paul Walsh, Arnaud Marchant, Ana Angulo, Thorsten Forster, Peter Ghazal
Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection...
2017: Frontiers in Immunology
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