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Membranes: a meeting point for lipids, proteins and therapies.

Escribá PV, González-Ros JM, Goñi FM, Kinnunen PK, Vigh L, Sánchez-Magraner L, Fernández AM, Busquets X, Horváth I, Barceló-Coblijn G - J. Cell. Mol. Med. (2008)

Bottom Line: Moreover, their alteration has been associated with the development of numerous diseases.The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs.In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane-lipid therapy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Cell Biomedicine, Dept of Biology-IUNICS, University of the Balearic Islands, Palma de Mallorca, Spain. pablo.escriba@uib.es

ABSTRACT
Membranes constitute a meeting point for lipids and proteins. Not only do they define the entity of cells and cytosolic organelles but they also display a wide variety of important functions previously ascribed to the activity of proteins alone. Indeed, lipids have commonly been considered a mere support for the transient or permanent association of membrane proteins, while acting as a selective cell/organelle barrier. However, mounting evidence demonstrates that lipids themselves regulate the location and activity of many membrane proteins, as well as defining membrane microdomains that serve as spatio-temporal platforms for interacting signalling proteins. Membrane lipids are crucial in the fission and fusion of lipid bilayers and they also act as sensors to control environmental or physiological conditions. Lipids and lipid structures participate directly as messengers or regulators of signal transduction. Moreover, their alteration has been associated with the development of numerous diseases. Proteins can interact with membranes through lipid co-/post-translational modifications, and electrostatic and hydrophobic interactions, van der Waals forces and hydrogen bonding are all involved in the associations among membrane proteins and lipids. The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs. In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane-lipid therapy.

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Inverted HII hexagonal phase composed of water-filled tubes with the lipid acyl chains pointing outwards. Different cellular membranes with a planar geometry invariably contain a variety of lipids and would therefore form such a phase. The presence of these lipids imparts frustration to the membrane, with a high packing density in the hydrocarbon region of the bilayer. Adapted from [51].
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fig04: Inverted HII hexagonal phase composed of water-filled tubes with the lipid acyl chains pointing outwards. Different cellular membranes with a planar geometry invariably contain a variety of lipids and would therefore form such a phase. The presence of these lipids imparts frustration to the membrane, with a high packing density in the hydrocarbon region of the bilayer. Adapted from [51].

Mentions: Another example of lipid-driven membrane demix-ing is provided by ceramide, which is involved in cellular signalling of apoptosis, programmed cell death [70]. This lipid has a pronounced tendency for self-association, caused by intermolecular hydrogen bonding, further promoted by the weak hydration of its headgroup and tight packing of the saturated hydrocarbon chains. The segregated ceramide-enriched phases have significantly elevated chain melting temperatures and are crystalline in nature at physiological temperature [71]. Accordingly, the properties of ceramide- and cholesterol-induced phases are distinctively different and they can be expected to have very different impacts on the lateral organization of membrane proteins, for instance. The tight packing of ceramide further manifests another important property characterizing membranes, bending rigidity, pertaining to the energy required to change the shape (curvature) of a membrane. Although membranes formed by unsaturated PCs, for instance, are very soft, with intense fluctuations in their shape caused by thermal energy, membranes enriched in ceramide are rigid. Ceramide illustrates also another important property of lipids, spontaneous curvature. More specifically, depending on their shapes [14] and more exactly, on their effective shapes [52], the curvature of the surfaces formed by lipids can be negative, zero or positive. Because of their small size and tight packing of the ceramide headgroups by intermolecular hydrogen bonding, ceramide-enriched membrane domains have negative spontaneous curvature, ultimately favouring the formation of the inverted hexagonal (HII) phase (Fig. 4). The negative spontaneous curvature of the ceramide-enriched membrane domains, together with their high bending rigidity, have interesting consequences, such as those given below. Ceramide can be enzymatically generated in membranes from SM, which has a strongly hydrated phosphocholine headgroup attached to ceramide. In contrast to ceramide, SM readily mixes at physiological temperatures with liquid disordered, unsaturated PCs. However, upon the conversion of SM to ceramide by sphingomyelinase (SMase), the reaction product segregates into microdomains [72] with negative spontaneous curvature and high bending rigidity. As a consequence, these microdomains start bending the membrane, ultimately causing shedding of ceramide-enriched vesicles from the original bilayer membrane [73, 74]. Accordingly, the formation of ceramide in biomembranes can be anticipated to cause lateral segregation of membrane constituents and be responsible for the membrane blebbing in apoptotic cells, in essence causing both 2-D as well as 3-D reorganization of membrane with its embedded proteins [75].


Membranes: a meeting point for lipids, proteins and therapies.

Escribá PV, González-Ros JM, Goñi FM, Kinnunen PK, Vigh L, Sánchez-Magraner L, Fernández AM, Busquets X, Horváth I, Barceló-Coblijn G - J. Cell. Mol. Med. (2008)

Inverted HII hexagonal phase composed of water-filled tubes with the lipid acyl chains pointing outwards. Different cellular membranes with a planar geometry invariably contain a variety of lipids and would therefore form such a phase. The presence of these lipids imparts frustration to the membrane, with a high packing density in the hydrocarbon region of the bilayer. Adapted from [51].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401130&req=5

fig04: Inverted HII hexagonal phase composed of water-filled tubes with the lipid acyl chains pointing outwards. Different cellular membranes with a planar geometry invariably contain a variety of lipids and would therefore form such a phase. The presence of these lipids imparts frustration to the membrane, with a high packing density in the hydrocarbon region of the bilayer. Adapted from [51].
Mentions: Another example of lipid-driven membrane demix-ing is provided by ceramide, which is involved in cellular signalling of apoptosis, programmed cell death [70]. This lipid has a pronounced tendency for self-association, caused by intermolecular hydrogen bonding, further promoted by the weak hydration of its headgroup and tight packing of the saturated hydrocarbon chains. The segregated ceramide-enriched phases have significantly elevated chain melting temperatures and are crystalline in nature at physiological temperature [71]. Accordingly, the properties of ceramide- and cholesterol-induced phases are distinctively different and they can be expected to have very different impacts on the lateral organization of membrane proteins, for instance. The tight packing of ceramide further manifests another important property characterizing membranes, bending rigidity, pertaining to the energy required to change the shape (curvature) of a membrane. Although membranes formed by unsaturated PCs, for instance, are very soft, with intense fluctuations in their shape caused by thermal energy, membranes enriched in ceramide are rigid. Ceramide illustrates also another important property of lipids, spontaneous curvature. More specifically, depending on their shapes [14] and more exactly, on their effective shapes [52], the curvature of the surfaces formed by lipids can be negative, zero or positive. Because of their small size and tight packing of the ceramide headgroups by intermolecular hydrogen bonding, ceramide-enriched membrane domains have negative spontaneous curvature, ultimately favouring the formation of the inverted hexagonal (HII) phase (Fig. 4). The negative spontaneous curvature of the ceramide-enriched membrane domains, together with their high bending rigidity, have interesting consequences, such as those given below. Ceramide can be enzymatically generated in membranes from SM, which has a strongly hydrated phosphocholine headgroup attached to ceramide. In contrast to ceramide, SM readily mixes at physiological temperatures with liquid disordered, unsaturated PCs. However, upon the conversion of SM to ceramide by sphingomyelinase (SMase), the reaction product segregates into microdomains [72] with negative spontaneous curvature and high bending rigidity. As a consequence, these microdomains start bending the membrane, ultimately causing shedding of ceramide-enriched vesicles from the original bilayer membrane [73, 74]. Accordingly, the formation of ceramide in biomembranes can be anticipated to cause lateral segregation of membrane constituents and be responsible for the membrane blebbing in apoptotic cells, in essence causing both 2-D as well as 3-D reorganization of membrane with its embedded proteins [75].

Bottom Line: Moreover, their alteration has been associated with the development of numerous diseases.The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs.In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane-lipid therapy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Cell Biomedicine, Dept of Biology-IUNICS, University of the Balearic Islands, Palma de Mallorca, Spain. pablo.escriba@uib.es

ABSTRACT
Membranes constitute a meeting point for lipids and proteins. Not only do they define the entity of cells and cytosolic organelles but they also display a wide variety of important functions previously ascribed to the activity of proteins alone. Indeed, lipids have commonly been considered a mere support for the transient or permanent association of membrane proteins, while acting as a selective cell/organelle barrier. However, mounting evidence demonstrates that lipids themselves regulate the location and activity of many membrane proteins, as well as defining membrane microdomains that serve as spatio-temporal platforms for interacting signalling proteins. Membrane lipids are crucial in the fission and fusion of lipid bilayers and they also act as sensors to control environmental or physiological conditions. Lipids and lipid structures participate directly as messengers or regulators of signal transduction. Moreover, their alteration has been associated with the development of numerous diseases. Proteins can interact with membranes through lipid co-/post-translational modifications, and electrostatic and hydrophobic interactions, van der Waals forces and hydrogen bonding are all involved in the associations among membrane proteins and lipids. The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs. In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane-lipid therapy.

Show MeSH
Related in: MedlinePlus