The lipid side of unfolded protein response Białek, Wojciech; Hryniewicz-Jankowska, Anita; Czechowicz, Paulina ...
Biochimica et biophysica acta. Molecular and cell biology of lipids,
October 2024, Volume:
1869, Issue:
7
Journal Article
Peer reviewed
Open access
Although our current knowledge of the molecular crosstalk between the ER stress, the unfolded protein response (UPR), and lipid homeostasis remains limited, there is increasing evidence that ...dysregulation of either protein or lipid homeostasis profoundly affects the other. Most research regarding UPR signaling in human diseases has focused on the causes and consequences of disrupted protein folding. The UPR itself consists of very complex pathways that function to not only maintain protein homeostasis, but just as importantly, modulate lipid biogenesis to allow the ER to adjust and promote cell survival. Lipid dysregulation is known to activate many aspects of the UPR, but the complexity of this crosstalk remains a major research barrier. ER lipid disequilibrium and lipotoxicity are known to be important contributors to numerous human pathologies, including insulin resistance, liver disease, cardiovascular diseases, neurodegenerative diseases, and cancer. Despite their medical significance and continuous research, however, the molecular mechanisms that modulate lipid synthesis during ER stress conditions, and their impact on cell fate decisions, remain poorly understood. Here we summarize the current view on crosstalk and connections between altered lipid metabolism, ER stress, and the UPR.
•ER lipid disequilibrium leads to numerous human pathologies.•There are bidirectional interactions between lipid homeostasis and the UPR.•All 3 sensors of the UPR contain sequences that recognize ER lipid changes.•Understanding this cross-talk could lead to novel therapeutic possibilities.
The major myelin protein expressed by the peripheral nervous system Schwann cells is protein zero (P0), which represents 50% of the total protein content in myelin. This 30-kDa integral membrane ...protein consists of an immunoglobulin (Ig)-like domain, a transmembrane helix, and a 69-residue C-terminal cytoplasmic tail (P0ct). The basic residues in P0ct contribute to the tight packing of myelin lipid bilayers, and alterations in the tail affect how P0 functions as an adhesion molecule necessary for the stability of compact myelin. Several neurodegenerative neuropathies are related to P0, including the more common Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS) as well as rare cases of motor and sensory polyneuropathy. We found that high P0ct concentrations affected the membrane properties of bicelles and induced a lamellar-to-inverted hexagonal phase transition, which caused bicelles to fuse into long, protein-containing filament-like structures. These structures likely reflect the formation of semicrystalline lipid domains with potential relevance for myelination. Not only is P0ct important for stacking lipid membranes, but time-lapse fluorescence microscopy also shows that it might affect membrane properties during myelination. We further describe recombinant production and low-resolution structural characterization of full-length human P0. Our findings shed light on P0ct effects on membrane properties, and with the successful purification of full-length P0, we have new tools to study the role of P0 in myelin formation and maintenance in vitro.
Display omitted
•The cytoplasmic domain of human myelin protein zero (P0ct) was observed to affect lipid membrane structure.•A bicelle-based model system allowed to detect phase changes in the lipid membrane.•P0ct caused changes in membrane morphology.•A combination of lamellar and non-lamellar phases was induced by P0ct, which may be relevant for its function in myelin.
Recent studies have shown that anesthetic agents alter the physical properties of lipid rafts on model membranes. However, if this destabilization occurs in brain membranes, altering the lipid ...raft-protein interaction, remains unknown. We analyzed the effects produced by pentobarbital (PB) on brain plasma membranes and lipid rafts in vivo. We characterized for the first time the thermotropic behavior of plasma membranes, synaptosomes, and lipid rafts from rat brain. We found that the transition temperature from the ordered gel to disordered liquid phase of lipids is close to physiological temperature. We then studied the effect of PB on protein composition of lipid rafts. Our results show a reduction of the total protein associated to rafts, with a higher reduction of the NMDAR compared to the GABAA receptor. Both receptors are considered the main targets of PB. In general, our results suggest that lipid rafts could be plausible mediators in anesthetic action.
Display omitted
•Pentobarbital alters the physical properties of lipid rafts on model membranes.•Lipid rafts could be plausible mediators in anesthetic action.•PB anesthesia decreases the amount of NMDAR in the lipid rafts fraction.
Tricyclic medicine such as amitriptyline (AMT) hydrochloride, initially developed to treat depression, is also used to treat neuropathic pain, anxiety disorder, and migraines. The mechanism of ...functioning of this type of drugs is ambiguous. Understanding the mechanism is important for designing new drug molecules with higher pharmacological efficiency. Hence, in the present study, biophysical approaches have been taken to shed light on their interactions with a model cellular membrane of brain sphingomyelin in the form of monolayer and multi-lamellar vesicles. The surface pressure-area isotherm infers the partitioning of a drug molecule into the lipid monolayer at the air water interface, providing a higher surface area per molecule and reducing the in-plane elasticity. Further, the surface electrostatic potential of the lipid monolayer is found to increase due to the insertion of drug molecule. The interfacial rheology revealed a reduction of the in-plane viscoelasticity of the lipid film, which, depends on the adsorption of the drug molecule onto the film. Small-angle X-ray scattering (SAXS) measurements on multilamellar vesicles (MLVs) have revealed that the AMT molecules partition into the hydrophobic core of the lipid membrane, modifying the organization of lipids in the membrane. The modified physical state of less rigid membrane and the transformed electrostatics of the membrane could influence its interaction with synaptic vesicles and neurotransmitters making higher availability of the neurotransmitters in the synaptic cleft.
Display omitted
•Understanding interaction of tricyclic drug with membrane helps developing new drug•Amitriptyline provides high area to lipid to reduce compressional modulus of membrane•Amitriptyline has positively charged surface, hence modifies membrane electrostatics•Amitriptyline helps fusion of synaptic vesicle by reducing bulk modulus of membrane•Amitriptyline helps repelling neurotransmitters to make available in synaptic cleft
The discovery of the endocannabinoid system (ECS) dates back only 30 years. Although many research groups have been elucidating its components, location, functions and metabolism, the peculiarities ...of the compounds considered "neurotransmitters" of ECS generate questions that have not yet been answered or controversies in the literature. In this context, we studied the molecular behaviour of the main endocannabinoid compounds and the main phytocannabinoids in eukaryotic outer and inner model membranes. The high lipophilicity of these compounds gives place to the hypothesis that cannabinoids may reach the molecular targets through the lipid bilayer. This consideration is not only for the cannabinoid receptors but also for other (many) targets that these bioactive molecules modulate (Watkins, 2019; Nelson et al., 2020; Jakowiecki and Filipek, 2016). Given the reported multitarget action of these compounds and the differential behaviour towards the different receptors, studying the properties and dynamics of these cannabinoids in POPC and POPE model membranes become relevant. In this regard, we have studied the differential modulation of the endocannabinoids anandamide and 2-arachidonoyl-glycerol and the phytocannabinoids cannabidiol and trans-Δ9-tetrahydrocannabinol to eukaryotic outer and inner model membranes. Results show that behaviours favour the mobility of the bioactive molecules studied by the external eukaryotic model membrane. As well as, the internal eukaryotic model membrane is less fluid, favouring the stabilisation of folded conformations or the positioning of the molecules in the centre of the bilayer. These results provide relevant evidence that contributes to a deep inside understanding of the behaviour of the primary endogenous ligands of ECS, together with the principal phytocannabinoids of C. sativa.
Display omitted
•Endo and phytocannabinoids present differential interaction with lipid membranes.•Cannabinoids increase the disorder of hydrocarbon chains of POPC lipid membranes.•Model membrane of POPE stabilizes folded conformers of anandamide.•2-Arachidonoyl-glycerol shows a low tendency to penetrate POPC lipid membranes.•CBD and THC present differential behaviour both in POPC and POPE lipid membrane.
Experimental evidence shows that the eye lens loses its elasticity dramatically with age. It has also been reported that the cholesterol (Chol) content in the eye lens fiber cell plasma membrane ...increases significantly with age. High Chol content leads to the formation of cholesterol bilayer domains (CBDs) in the lens membrane. The role of high Chol associated with lens elasticity is unclear. The purpose of this research is to investigate the membrane elasticity of the model of porcine lens-lipid (MPLL) membrane with increasing Chol content to elucidate the role of high Chol in lens membrane elasticity. In this study, we used atomic force microscopy (AFM) to study the mechanical properties (breakthrough force and area compressibility modulus (KA)) of the MPLL membrane with increasing Chol content where KA is the measure of membrane elasticity. We varied Chol concentration in Chol/MPLL membrane from 0 to ∼71 mol%. Supported Chol/MPLL membranes were prepared by fusion of small unilamellar vesicles (SUVs) on top of a flat mica surface. SUVs of the Chol/MPLL lipid mixture were prepared with the rapid solvent exchange method followed by probe-tip sonication. For the Chol/MPLL mixing ratio of 0, AFM image showed the formation of two distinct phases of the membrane, i.e., liquid-disordered phase (ld) and solid-ordered phase (so) membrane. However, with Chol/MPLL mixing ratio of 0.5 and above, only liquid-ordered phase (lo) membrane was formed. Also, two distinct breakthrough forces corresponding to ld and so were observed for Chol/MPLL mixing ratio of 0, whereas only one breakthrough force was observed for membranes with Chol/MPLL mixing ratio of 0.5 and above. No significant difference in the membrane surface roughness was measured with increasing Chol content for these membranes; however, breakthrough force and KA for lo membrane increased when Chol/MPLL mixing ratio was increased from 0.5 to 1. Interestingly above the Chol/MPLL mixing ratio of 1, both breakthrough force and KA decreased, indicating the formation of CBDs. Furthermore, these results showed that membrane elasticity increases at high Chol content, suggesting that high Chol content in lens membrane might be responsible for maintaining lens membrane elasticity.
•AFM studies of a model of porcine lens-lipid membrane.•Mechanical properties of the model lens-lipid membrane are modulated by cholesterol.•High cholesterol increases the membrane elasticity of a model lens-lipid membrane.•High cholesterol in the lens may protect against the progression of lens hardening.
Understanding interactions of inorganic nanoparticles with biomolecules is important in many biotechnology, nanomedicine, and toxicological research, however, the size of typical nanoparticles makes ...their direct modeling by atomistic simulations unfeasible. Here, we present a bottom‐up coarse‐graining approach for modeling titanium dioxide (TiO 2) nanomaterials in contact with phospholipids that uses the inverse Monte Carlo method to optimize the effective interactions from the structural data obtained in small‐scale all‐atom simulations of TiO 2 surfaces with lipids in aqueous solution. The resulting coarse‐grained models are able to accurately reproduce the structural details of lipid adsorption on different titania surfaces without the use of an explicit solvent, enabling significant computational resource savings and favorable scaling. Our coarse‐grained simulations show that small spherical TiO 2 nanoparticles (r=2 nm) can only be partially wrapped by a lipid bilayer with phosphoethanolamine headgroups, however, the lipid adsorption increases with the radius of the nanoparticle. The current approach can be used to study the effect of the size and shape of TiO 2 nanoparticles on their interactions with cell membrane lipids, which can be a determining factor in membrane wrapping as well as the recently discovered phenomenon of nanoquarantining, which involves the formation of layered nanomaterial–lipid structures.
Computational methods have become an important tool in studying the mechanisms of nanomaterial exposure. However, while the simulations of nanoparticles interacting with biomatter at atomic resolution are exceptionally detailed, computing power becomes a bottleneck with the increasing size of simulated systems. Here we present a coarse‐grained model of TiO 2 nanomaterials in contact with cell membrane phospholipids, which is significantly faster yet captures the structural detail from atomistic simulations with the help of the inverse Monte Carlo method.
Lipid composition of the cancer cell membrane Szlasa, Wojciech; Zendran, Iga; Zalesińska, Aleksandra ...
Journal of bioenergetics and biomembranes,
10/2020, Volume:
52, Issue:
5
Journal Article
Peer reviewed
Open access
Cancer cell possesses numerous adaptations to resist the immune system response and chemotherapy. One of the most significant properties of the neoplastic cells is the altered lipid metabolism, and ...consequently, the abnormal cell membrane composition. Like in the case of phosphatidylcholine, these changes result in the modulation of certain enzymes and accumulation of energetic material, which could be used for a higher proliferation rate. The changes are so prominent, that some lipids, such as phosphatidylserines, could even be considered as the cancer biomarkers. Additionally, some changes of biophysical properties of cell membranes lead to the higher resistance to chemotherapy, and finally to the disturbances in signalling pathways. Namely, the increased levels of certain lipids, like for instance phosphatidylserine, lead to the attenuation of the immune system response. Also, changes in lipid saturation prevent the cells from demanding conditions of the microenvironment. Particularly interesting is the significance of cell membrane cholesterol content in the modulation of metastasis. This review paper discusses the roles of each lipid type in cancer physiology. The review combined theoretical data with clinical studies to show novel therapeutic options concerning the modulation of cell membranes in oncology.
Natural membrane vesicles, including extracellular vesicles and enveloped viruses, participate in various events in vivo. To study and manipulate these events, biomembrane‐coated nanoparticles ...inspired by natural membrane vesicles are developed. Herein, an efficient method is presented to prepare organic–inorganic hybrid materials in high yields that can accommodate various lipid compositions and particle sizes. To demonstrate this method, silica nanoparticles are passed through concentrated lipid layers prepared using density gradient centrifugation, followed by purification, to obtain lipid membrane‐coated nanoparticles. Various lipids, including neutral, anionic, and cationic lipids, are used to prepare concentrated lipid layers. Single‐particle analysis by imaging flow cytometry determines that silica nanoparticles are uniformly coated with a single lipid bilayer. Moreover, cellular uptake of silica nanoparticles is enhanced when covered with a lipid membrane containing cationic lipids. Finally, cell‐free protein expression is applied to embed a membrane protein, namely the Spike protein of severe acute respiratory syndrome coronavirus 2, into the coating of the nanoparticles, with the correct orientation. Therefore, this method can be used to develop organic–inorganic hybrid nanomaterials with an inorganic core and a virus‐like coating, serving as carriers for targeted delivery of cargos such as proteins, DNA, and drugs.
Here, nanoparticles are efficiently coated with a lipid bilayer by passing them through a concentrated lipid layer prepared by density gradient centrifugation. In addition, a new approach for the synthesis of bioinorganic hybrid nanomaterials is demonstrated by applying cell‐free protein expression to embed membrane proteins, the Spike protein of severe acute respiratory syndrome coronavirus 2, into coatings of the nanoparticles.
Understanding the thermodynamic and kinetic properties of biomolecules requires elucidation of their complex energy landscape. A disconnectivity graph analysis of the energy landscape provides a ...framework for mapping the multi-dimensional landscape onto a two-dimensional representation while preserving the key features of the energy landscape. Several studies show that the structure or shape of the disconnectity graph is directly associated with the function of protein and nucleic acid molecules. In this review, we discuss how disconnectivity analysis of the potential energy surface can be extended to lipid molecules to glean important information about membrane organization. The shape of the disconnectivity graphs can be used to predict the lateral organization of multi-component lipid bilayer. We hope that this review encourages the use of disconnectivity graphs routinely by membrane biophysicists to predict the lateral organization of lipids.
Display omitted
•The disconnectivity graph analysis is a reliable tool to represent complex free energy landscape of biomolecular systems.•Usually applied to study proteins and nucleic acids conformational landscapes.•Here we show the shape of the disconnectivity graphs can be used to predict the lateral organization of multi-component lipid bilayer.•Nature of lipid diffusion in membrane can be understood from cage breaking analysis of the disconnectivity graph.
PDF
