Properties of Palmitoyl Phosphatidylcholine, Sphingomyelin, and Dihydrosphingomyelin Bilayer Membranes as Reported by Different Fluorescent Reporter Molecules

Nyholm, Thomas K.M.; Nylund, Matts; Soderholm, A.; Slotte, J. Peter

doi:10.1016/s0006-3495(03)74915-7

Cited by 71 publications

(57 citation statements)

References 62 publications

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“…We then used the average intersect point of these curves to provide an estimate of the transition temperature. This method gave a result of 311.9±2.8 K which is in good agreement of the experimental range of 311 K-314.5 K (most experiments give the exact value as 314.5 K) [101,44,102,103,104]. While the system setup here involved over five times as many lipids as what was used to determine the transition temperatures of PCs, this method shows that at reasonable accurate estimate of the transition temperature can be obtained using only 25 ns simulations as opposed to 100 ns simulations used in simulations of PCs [130].…”

Section: Discussionsupporting

confidence: 82%

“…For example palmitoyl is predominantly found in erythrocytes [43], while stearoyl is more common in nervous tissue [44,45]. With regard to the lateral distribution of sphingomyelin experimental anal- [44], whereas the transition temperature for PSM is between 311 K-314.5 K (38°C-41.5°C) [101,44,102,103,104]. Experimentally cholesterol is observed to preferentially co-localise with sphingomyelins over phosphatidylcholines [105].…”

Section: Introductionmentioning

confidence: 99%

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Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Corbett¹

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The ability of a cell to recognise and respond to external stimuli is essential for cell survival and growth. Type-I cytokine receptors regulate many inflammatory, homeostatic, and growth and development signalling pathways. For example, the erythropoietin receptor is the main driver of red blood cell production from stem cells. All type-I cytokine receptors consist of an extracellular ligandbinding domain, a single helical transmembrane domain and an intracellular domain that associates with kinase/transcription factor signalling pathway, for example the JAK2/STAT5 pathway. Despite being extensively studied and structures of the extracellular domains of many of these receptors being known, the precise mechanism by which these receptors couple the event of ligand-binding to intracellular activation is not known. Indeed, multiple mechanisms have been proposed from experimental and crystallographic data for different receptors. For example, the activation of the growth hormone receptor is proposed to involve a relative rotation of two receptor chains, while in the case of the erythropoietin receptor the chains were suggested to separate in a scissor-like mechanism. In part, this is due to the limits of resolution achievable by experimental approaches as well as a lack of appreciation for the dynamical properties of the receptor proteins and the membrane environment.This thesis focuses on the use of fully atomistic molecular dynamics simulations to investigate the mechanism of activation for the type-I cytokine receptors. In particular MD simulations are used to probe whether conformations of the receptors observed crystallographically are representative of physiological conformations. Further to this, the quality of the X-ray crystal structures is tested by recreation of the crystal lattice in MD simulations. The effect of membrane composition is investigated by comparing the behaviour of the transmembrane domain in bulk and cholesterol-enriched raft-like bilayers. Finally, receptor dimers are examined for active and inactive conformations in raft-like bilayers containing sphingomyelin. Force field parameters for the lipid sphingomyelin that were used to build raft-like bilayers were also generated and validated. The work draws into question several of the mechanistic models proposed for the type-I cytokine receptors and demonstrates the difficulty in proposing a detailed mechanism of action based on limited sets of structural data. In particular, they highlight the limitations of the use of structural data in proposing a model when only a part of the receptor is considered. Results from the simulations also suggest that the lipid composition can influence the structure and behaviour of the receptors. Taken together the work shows the importance of considering not only the ligand-binding domain of the receptor but also the restrictions imposed by the transmembrane domain and structural influences caused by the membrane when proposing a mechanism of activation for this important class of cell surface recept...

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Corbett¹

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“…Lipid packing can be determined with fluorescent membrane probes such as 6-dodecanoyl-2-dimethylaminonaphthalene (Laurdan) (28)(29)(30). When integrated into the bilayer, the wavelength of the emission peak of the dye is dependent on the presence of water in the membrane.…”

mentioning

confidence: 99%

“…Despite its many applications in model (30,32) and cellular membranes (29,33,34), Laurdan has some disadvantages on a methodological level, including low solubility in aqueous media, low fluorescence intensity, and photo-bleaching, which were overcome by the addition of a carboxyl-headgroup (6-dodecanoyl-2-methylcarboxymethylaminonaphthalene; C-laurdan) (35).…”

mentioning

confidence: 99%

Order of lipid phases in model and plasma membranes

Kaiser

Lingwood

Levental

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

417

396

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Lipid rafts are nanoscopic assemblies of sphingolipids, cholesterol, and specific membrane proteins that contribute to lateral heterogeneity in eukaryotic membranes. Separation of artificial membranes into liquid-ordered (Lo) and liquid-disordered phases is regarded as a common model for this compartmentalization. However, tight lipid packing in Lo phases seems to conflict with efficient partitioning of raft-associated transmembrane (TM) proteins. To assess membrane order as a component of raft organization, we performed fluorescence spectroscopy and microscopy with the membrane probes Laurdan and C-laurdan. First, we assessed lipid packing in model membranes of various compositions and found cholesterol and acyl chain dependence of membrane order. Then we probed cell membranes by using two novel systems that exhibit inducible phase separation: giant plasma membrane vesicles [Baumgart et al. (2007) Proc Natl Acad Sci USA 104:3165-3170] and plasma membrane spheres. Notably, only the latter support selective inclusion of raft TM proteins with the ganglioside GM1 into one phase. We measured comparable small differences in order between the separated phases of both biomembranes. Lateral packing in the ordered phase of giant plasma membrane vesicles resembled the Lo domain of model membranes, whereas the GM1 phase in plasma membrane spheres exhibited considerably lower order, consistent with different partitioning of lipid and TM protein markers. Thus, lipid-mediated coalescence of the GM1 raft domain seems to be distinct from the formation of a Lo phase, suggesting additional interactions between proteins and lipids to be effective.generalized polarization value ͉ giant unilamellar vesicle ͉ membrane organization ͉ lipid sorting ͉ lipid raft T he lipid raft hypothesis postulates that selective interactions among sphingolipids, cholesterol, and membrane proteins contribute to lateral membrane heterogeneity (1). A tenet of the model is that small, dynamic cholesterol-sphingolipid-enriched assemblies can be induced to coalesce into larger, more stable structures through clustering of domain components (2). Although experimental data support cholesterol-dependent nano-scale membrane heterogeneity (3-8) and selective domain formation upon raft cross-linking (9-12), the mechanisms that govern such associations in cell membranes remain unclear.On the molecular level, a key feature that is thought to contribute to raft assembly is the propensity of cholesterol to pack tightly with saturated acyl chains of lipids causing them to adopt an extended conformation (13,14). In multi-component model membranes (n Ͼ 2), this interaction can lead to microscopically separate fluid membrane phases: the liquid-ordered (Lo) phase, enriched in saturated (sphingo-)lipids and cholesterol in a highly condensed state, and the liquid-disordered (Ld) phase, enriched in unsaturated glycerophospholipid in a disordered state (15)(16)(17).Several features of the Lo phase in model membranes correspond to the predicted properties of lipid rafts in cel...

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“…Partitioning is also important because the immediate probe environment is the most significant factor affecting fluorescence intensity. While we do not know the extent to which DPH and β-DPH HPC are segregated in the DPPC/F-DPPC and DAPC/F-DPPC systems, phospholipid-bound DPH derivatives are generally more prone to partitioning into domains while DPH is homogeneously distributed [43,[45][46][47]. Most importantly, the intensity of free DPH and β-DPH HPC always decreases in the L β I phase.…”

Section: Fluorophore Behaviormentioning

confidence: 99%

Properties of phosphatidylcholine in the presence of its monofluorinated analogue

Smith

Gorkum

Dea

2010

Biophysical Chemistry

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Properties of Palmitoyl Phosphatidylcholine, Sphingomyelin, and Dihydrosphingomyelin Bilayer Membranes as Reported by Different Fluorescent Reporter Molecules

Cited by 71 publications

References 62 publications

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Order of lipid phases in model and plasma membranes

Properties of phosphatidylcholine in the presence of its monofluorinated analogue

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