Ceramide structure dictates glycosphingolipid nanodomain assembly and function.
Ontology highlight
ABSTRACT:
SUBMITTER: Arumugam S
PROVIDER: S-EPMC8209009 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:An aureolic acid natural product mithramycin (MTM) has been known for its potent antineoplastic properties. MTM inhibits cell growth by binding in the minor groove of double-stranded DNA as a dimer, in which the two molecules of MTM are coordinated to each other through a divalent metal ion. A crystal structure of an MTM analogue, MTM SA-Phe, in the active metal ion-coordinated dimeric form demonstrates how the stereochemical features of MTM define the helicity of the dimeric scaffold for its binding to a right-handed DNA double helix. We also show crystallographically and biochemically that MTM, but not MTM SA-Phe, can be inactivated by boric acid through formation of a large macrocyclic species, in which two molecules of MTM are crosslinked to each other through 3-side chain-boron-sugar intermolecular bonds. We discuss these structural and biochemical properties in the context of MTM biosynthesis and the design of MTM analogues as anticancer therapeutics.
| S-EPMC6533888 | biostudies-literature
Project description:In this work we present a comprehensive study of the domain structure of a nickel oxide single crystal grown by floating zone melting and suggest a correlation between point defects and the observed domain structure. The properties and structure of domains dictate the dynamics of resistive switching, water splitting and gas sensing, to name but a few. Investigating the correlation between point defects and domain structure can provide a deeper understanding of their formation and structure, which potentially allows one to tailor domain structure and the dynamics of the aforementioned applications. A range of inhomogeneities are observed by diffraction and microscopy techniques. X-ray and low-energy electron diffraction reveal domains on the submicron- and nanometer-scales, respectively. In turn, these domains are visualised by atomic force and scanning tunneling microscopy (STM), respectively. A comprehensive transmission electron microscopy (TEM) study reveals inhomogeneities ranging from domains of varying size, misorientation of domains, variation of the lattice constant and bending of lattice planes. X-ray photoelectron spectroscopy and electron energy-loss spectroscopy indicate the crystal is Ni deficient. Density functional theory calculations-considering the spatial and electronic disturbance induced by the favourable nickel vacancy-reveal a nanoscale distortion comparable to STM and TEM observations. The different inhomogeneities are understood in terms of the structural relaxation induced by ordering of nickel vacancies, which is predicted to be favourable.
| S-EPMC7875979 | biostudies-literature
Project description:Structural and morphological interplay between hard and soft phases determine the bulk properties of thermoplastic polyurethanes. Commonly employed techniques rely on different physical or chemical phenomena for characterizing the organization of domains, but detailed structural information can be difficult to derive. Here, total scattering pair distribution function (PDF) analysis is used to determine atomic-scale insights into the connectivity and molecular ordering and compared to the domain size and morphological characteristics measured by AFM, TEM, SAXS, WAXS, and solid-state NMR 1H-1H spin-diffusion. In particular, density distribution functions are highlighted as a means to bridging the gap from the domain morphology to intradomain structural ordering. High real-space resolution PDFs are shown to provide a sensitive fingerprint for indexing aromatic, aliphatic, and polymerization-induced bonding characteristics, as well as the hard phase structure, and indicate that hard phases coexist in both ordered and disordered states.
| S-EPMC7594411 | biostudies-literature
Project description:Silver nanomaterials have potent antibacterial properties that are the foundation for their wide commercial use as well as for concerns about their unintended environmental impact. The nanoparticles themselves are relatively biologically inert but they can undergo oxidative dissolution yielding toxic silver ions. A quantitative relationship between silver material structure and dissolution, and thus antimicrobial activity, has yet to be established. Here, this dissolution process and associated biological activity is characterized using uniform nanoparticles with variable dimension, shape, and surface chemistry. From this, a phenomenological model emerges that quantitatively relates material structure to both silver dissolution and microbial toxicity. Shape has the most profound influence on antibacterial activity, and surprisingly, surface coatings the least. These results illustrate how material structure may be optimized for antimicrobial properties and suggest strategies for minimizing silver nanoparticle effects on microbes.
| S-EPMC9249613 | biostudies-literature
Project description:Professional secretory cells can produce large amounts of high-quality complex molecules, including IgM antibodies. Owing to their multivalency, polymeric IgM antibodies provide an efficient first-line of defense against pathogens. To decipher the mechanisms of IgM assembly, we investigated its biosynthesis in living cells and faithfully reconstituted the underlying processes in vitro. We find that a conserved peptide extension at the C-terminal end of the IgM heavy (Ig-?) chains, termed the tailpiece, is necessary and sufficient to establish the correct geometry. Alanine scanning revealed that hydrophobic amino acids in the first half of the tailpiece contain essential information for generating the correct topology. Assembly is triggered by the formation of a disulfide bond linking two tailpieces. This induces conformational changes in the tailpiece and the adjacent domain, which drive further polymerization. Thus, the biogenesis of large and topologically challenging IgM complexes is dictated by a local conformational switch in a peptide extension.
| S-EPMC5642677 | biostudies-literature
Project description:Recent studies have reported that glycosphingolipids (GSL) might be involved in obesity induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin sensitivity accompanied with improved glycemic control leading to decreased liver steatosis in obese mice. In addition, GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL-biosynthesis have been used to inhibit function of the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide based GSL-synthesis pathway. In the present study, a genetic approach for GSL deletion in hepatocytes was chosen to achieve full inhibition of GSL synthesis and to prevent possible adverse effects caused by Ugcg-inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change quantity of bile excretion through the biliary duct. Total bile salt content in bile-, feces- and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver-, bile-, feces- and plasma-samples remained unaffected. Lipoprotein concentration in plasma-samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL-deficiency on development of liver steatosis after high fat diet feeding could not be observed. Conclusion: The data suggest that GSL in hepatocytes are not essential for sterol, glucose and lipoprotein metabolism and do not prevent high fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types. Comparison of wildtype mouse liver function versus Ugcg-deficient
2010-05-14 | E-GEOD-19316 | biostudies-arrayexpress
Project description:Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. The rafts at the cell surface play important functions in signal transduction. Recent reports have demonstrated that lipid rafts are spatially and compositionally heterogeneous in the single-cell membrane. In this review, we summarize our recent data on living platelets using two specific probes of raft components: lysenin as a probe of sphingomyelin-rich rafts and BC? as a probe of cholesterol-rich rafts. Sphingomyelin-rich rafts that are spatially and functionally distinct from the cholesterol-rich rafts were found at spreading platelets. Fibrin is translocated to sphingomyelin-rich rafts and platelet sphingomyelin-rich rafts act as platforms where extracellular fibrin and intracellular actomyosin join to promote clot retraction. On the other hand, the collagen receptor glycoprotein VI is known to be translocated to cholesterol-rich rafts during platelet adhesion to collagen. Furthermore, the functional roles of platelet glycosphingolipids and platelet raft-binding proteins including G protein-coupled receptors, stomatin, prohibitin, flotillin, and HflK/C-domain protein family, tetraspanin family, and calcium channels are discussed.
| S-EPMC7432685 | biostudies-literature
Project description:A possible role of ceramide in defining the carbohydrate structure of glycolipids and the expression of glycolipid function has been proposed, on the basis of our finding that the ceramide composition of "lacto-series" glycosphingolipid isolated from human erythrocytes shows a remarkable correlation with the terminal carbohydrate structure: (i) The ceramides of three glycosphingolipids with Lex (or x) determinant [Gal beta 1 leads to 4(Fuc alpha 1 leads to 3) GlcNAc] had almost exclusively 16:0 fatty acid; in contrast, the ceramide of its positional isomer H determinant had mainly 20--24:0 fatty acids. (ii) The ceramide of two glycosphingolipids with NeuAc alpha 2 leads to 6GAL structure was predominantly of 16:0 fatty acid, in contrast to that of its positional isomer NeuAc alpha 2 leads to 3Gal residue, in which the ceramide had 20--24:0 fatty acids. These results, together with our previous observation that ceramide composition of mouse lymphoma and myelocytic leukemia MI cells affects their antigenicity, suggest that ceramide structure may define the organization of glycosyltransferase for synthesis of the carbohydrate determinants and may affect the organization and orientation of the carbohydrate chain in membranes, eliciting or suppressing the reactivity to its ligand. Because these glycolipids with Lex and NeuAc alpha 2 leads to 6Gal structures are developmentally regulated and are highly expressed in certain tumors, ceramide composition may affect development, differentiation, and oncogenesis.
| S-EPMC346442 | biostudies-literature
Project description:Recent studies have reported that glycosphingolipids (GSL) might be involved in obesity induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin sensitivity accompanied with improved glycemic control leading to decreased liver steatosis in obese mice. In addition, GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL-biosynthesis have been used to inhibit function of the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide based GSL-synthesis pathway. In the present study, a genetic approach for GSL deletion in hepatocytes was chosen to achieve full inhibition of GSL synthesis and to prevent possible adverse effects caused by Ugcg-inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change quantity of bile excretion through the biliary duct. Total bile salt content in bile-, feces- and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver-, bile-, feces- and plasma-samples remained unaffected. Lipoprotein concentration in plasma-samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL-deficiency on development of liver steatosis after high fat diet feeding could not be observed. Conclusion: The data suggest that GSL in hepatocytes are not essential for sterol, glucose and lipoprotein metabolism and do not prevent high fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types.
2010-02-04 | GSE19316 | GEO
Project description:Deciphering the significance of length, sequence, and stereochemistry in block copolymer self-assembly remains an ongoing challenge. A dearth of methods to access uniform block co-oligomers/polymers with precise stereochemical sequences has precluded such studies. Here, we develop iterative exponential growth methods for the synthesis of a small library of unimolecular stereoisomeric diblock 32-mers. X-ray scattering reveals that stereochemistry modulates the phase behavior of these polymers, which we rationalize based on simulations carried out on a theoretical model system. This work demonstrates that stereochemical sequence can play a crucial role in unimolecular polymer self-assembly.
| S-EPMC5803323 | biostudies-literature