Bacteria and eukaryotic cells contain geometry-sensing tools in their cytosol: protein motifs or domains that recognize the curvature, concave or convex, deep or shallow, of lipid membranes. These ...sensors contrast with classical lipid-binding domains by their extended structure and, sometimes, counterintuitive chemistry. Among the sensors are long amphipathic helices, such as the ALPS motif and the N-terminal region of α-synuclein, whose apparent "design defects" translate into a remarkable ability to specifically adsorb to the surface of small vesicles. Fundamental differences in the lipid composition of membranes of the early and late secretory pathways probably explain why some sensors use mostly electrostatics whereas others take advantage of the hydrophobic effect. Membrane curvature sensors help to organize very diverse reactions, such as lipid transfer between membranes, the tethering of vesicles at the Golgi apparatus, and the assembly-disassembly cycle of protein coats.
Whereas some rare lipids contribute to the identity of cell organelles, we focus on the abundant lipids that form the matrix of organelle membranes. Observations using bioprobes and peripheral ...proteins, notably sensors of membrane curvature, support the prediction that the cell contains two broad membrane territories: the territory of loose lipid packing, where cytosolic proteins take advantage of membrane defects, and the territory of electrostatics, where proteins are attracted by negatively charged lipids. The contrasting features of these territories provide specificity for reactions occurring along the secretory pathway, on the plasma membrane, and also on lipid droplets and autophagosomes.
Numerous data have been collected on lipid-binding amphipathic helices involved in membrane-remodeling machineries and vesicular transport. Here we describe how, with regard to lipid composition, the ...physicochemical features of some amphipathic helices explain their ability to recognize membrane curvature or to participate in membrane remodeling. We propose that sensing highly-curved membranes requires that the polar and hydrophobic faces of the helix do not cooperate in lipid binding. A more detailed description of the interaction between amphipathic helices and lipids is however needed; notably to explain how new helices contribute to detection of modest changes in curvature or even negative curvature.
To maintain an asymmetric distribution of ions across membranes, protein pumps displace ions against their concentration gradient by using chemical energy. Here, we describe a functionally analogous ...but topologically opposite process that applies to the lipid transfer protein (LTP) oxysterol-binding protein (OSBP). This multidomain protein exchanges cholesterol for the phosphoinositide phosphatidylinositol 4-phosphate PI(4)P between two apposed membranes. Because of the subsequent hydrolysis of PI(4)P, this counterexchange is irreversible and contributes to the establishment of a cholesterol gradient along organelles of the secretory pathway. The facts that some natural anti-cancer molecules block OSBP and that many viruses hijack the OSBP cycle for the formation of intracellular replication organelles highlight the importance and potency of OSBP-mediated lipid exchange. The architecture of some LTPs is similar to that of OSBP, suggesting that the principles of the OSBP cycle-burning PI(4)P for the vectorial transfer of another lipid-might be general.
Biological membranes are complex and dynamic assemblies of lipids and proteins. Poikilothermic organisms including bacteria, fungi, reptiles, and fish do not control their body temperature and must ...adapt their membrane lipid composition in order to maintain membrane fluidity in the cold. This adaptive response was termed homeoviscous adaptation and has been frequently studied with a specific focus on the acyl chain composition of membrane lipids. Massspectrometry-based lipidomics can nowadays provide more comprehensive insights into the complexity of lipid remodeling during adaptive responses. Eukaryotic cells compartmentalize biochemical processes in organelles with characteristic surface properties, and the lipid composition of organelle membranes must be tightly controlled in order to maintain organelle function and identity during adaptive responses. Some highly differentiated cells such as neurons maintain unique lipid compositions with specific physicochemical properties. To date little is known about the sensory mechanisms regulating the acyl chain profile in such specialized cells or during adaptive responses. Here we summarize our current understanding of lipid metabolic networks with a specific focus on the role of physicochemical membrane properties for the regulation of the acyl chain profile during homeoviscous adaptation. By comparing the mechanisms of the bacterial membrane sensors with the prototypical eukaryotic lipid packing sensor Mga2 fromSaccharomyces cerevisiae,we identify common operational principles that might guide our search for novel membrane sensors in different organelles, organisms, and highly specialized cells.
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•Physical membrane properties and biosynthesis of membrane lipids are interdependent.•Tailored production of lipid molecules ensures membrane homeostasis.•Comparative analysis of the homeoviscous adaptation reveals common features.•Molecular lipid packing sensors use relative TMH rotations as a sensitive mechanism.
Highlights • Membrane bound organelles differ by the acyl chain profile of their phospholipids. • Monounsaturated phospholipids and curvature cooperate to create lipid-packing defects. • ...Polyunsaturated phospholipids have no intrinsic shape and correct lipid-packing defects. • Polyunsaturated phospholipids soften fast mechanical stresses (e.g., curvature).
The counterflow transport of sterols and PI4P Mesmin, Bruno; Antonny, Bruno
Biochimica et biophysica acta,
August 2016, 2016-Aug, 2016-08-00, Letnik:
1861, Številka:
8
Journal Article
Recenzirano
Cholesterol levels in intracellular membranes are constantly adjusted to match with specific organelle functions. Cholesterol is kept high in the plasma membrane (PM) because it is essential for its ...barrier function, while low levels are found in the endoplasmic reticulum (ER) where cholesterol mediates feedback control of its own synthesis by sterol-sensor proteins. The ER→Golgi→PM concentration gradient of cholesterol in mammalian cells, and ergosterol in yeast, appears to be sustained by specific intracellular transport processes, which are mostly mediated by lipid transfer proteins (LTPs). Here we review a recently described function of two LTPs, OSBP and its yeast homolog Osh4p, which consists in creating a sterol gradient between membranes by vectorial transport. OSBP also contributes to the formation of ER/Golgi membrane contact sites, which are important hubs for the transfer of several lipid species. OSBP and Osh4p organize a counterflow transport of lipids whereby sterols are exchanged for the phosphoinositide PI4P, which is used as a fuel to drive sterol transport. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.
•OSBP and Osh4p create sterol gradients between membranes by vectorial transport.•OSBP contributes to the formation of ER/Golgi membrane contact sites.•The phosphoinositide PI4P is used as a fuel to drive sterol transport.
Lipids are unevenly distributed within eukaryotic cells, thus defining organelle identity. How non-vesicular transport mechanisms generate these lipid gradients between membranes remains a central ...question. Here using quantitative, real-time lipid transport assays, we demonstrate that Osh4p, a sterol/phosphatidylinositol-4-phosphate (PI(4)P) exchanger of the ORP/Osh family, transports sterol against its gradient between two membranes by dissipating the energy of a PI(4)P gradient. Sterol transport is sustained through the maintenance of this PI(4)P gradient by the PI(4)P-phosphatase Sac1p. Differences in lipid packing between membranes can stabilize sterol gradients generated by Osh4p and modulate its lipid exchange capacity. The ability of Osh4p to recognize sterol and PI(4)P via distinct modalities and the dynamics of its N-terminal lid govern its activity. We thus demonstrate that an intracellular lipid transfer protein actively functions to create a lipid gradient between membranes.
Two parameters of biological membranes, curvature and lipid composition, direct the recruitment of many peripheral proteins to cellular organelles. Although these traits are often studied ...independently, it is their combination that generates the unique interfacial properties of cellular membranes. Here, we use a combination of in vivo, in vitro and in silico approaches to provide a comprehensive map of how these parameters modulate membrane adhesive properties. The correlation between the membrane partitioning of model amphipathic helices and the distribution of lipid-packing defects in membranes of different shape and composition explains how macroscopic membrane properties modulate protein recruitment by changing the molecular topography of the membrane interfacial region. Furthermore, our results suggest that the range of conditions that can be obtained in a cellular context is remarkably large because lipid composition and curvature have, under most circumstances, cumulative effects.
Phospholipid membranes form cellular barriers but need to be flexible enough to divide by fission. Phospholipids generally contain a saturated fatty acid (FA) at position
whereas the
-FA is ...saturated, monounsaturated or polyunsaturated. Our understanding of the impact of phospholipid unsaturation on membrane flexibility and fission is fragmentary. Here, we provide a comprehensive view of the effects of the FA profile of phospholipids on membrane vesiculation by dynamin and endophilin. Coupled to simulations, this analysis indicates that: (i) phospholipids with two polyunsaturated FAs make membranes prone to vesiculation but highly permeable; (ii) asymmetric
-saturated-
-polyunsaturated phospholipids provide a tradeoff between efficient membrane vesiculation and low membrane permeability; (iii) When incorporated into phospholipids, docosahexaenoic acid (DHA; omega-3) makes membranes more deformable than arachidonic acid (omega-6). These results suggest an explanation for the abundance of
-saturated-
-DHA phospholipids in synaptic membranes and for the importance of the omega-6/omega-3 ratio on neuronal functions.
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