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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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Phospholipase cascade of PLD activation and amplification of diacylglycerol production. Abbreviations: PI-PLC, phosphatidylinositol-specific phospholipase C; DG, diacylglyerol; PC, phosphatidylcholine; PA, phosphatidic acid; PKC, protein kinase C; PIP2, PI-4,5-bisphosphate and PIP kinase, PI phosphate kinase. Adapted from [100].
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fig06: Phospholipase cascade of PLD activation and amplification of diacylglycerol production. Abbreviations: PI-PLC, phosphatidylinositol-specific phospholipase C; DG, diacylglyerol; PC, phosphatidylcholine; PA, phosphatidic acid; PKC, protein kinase C; PIP2, PI-4,5-bisphosphate and PIP kinase, PI phosphate kinase. Adapted from [100].

Mentions: An additional degree of complexity in membrane lipid functions lies in the metabolic relationship between phospholipid species. There is a relatively large number of phospholipases and phosphatases that specifically participate in the interconversion of phospholipids and that in turn, can modulate the activity of those enzymes. The cascade of phospholipase D (PLD) activation is a clear example of this complexity (Fig. 6) [100]. The initial step of the cascade involves the agonist-induced and GPCR-mediated activation of phospholipase C (PLC) to hydrolyze phosphatidylinositol (PIP2) into DAG and IP3. The former activates PKC and the latter induces the release of Ca2+ into the cytosol through IP3-activated channels, which also activates PKC [101]. Interestingly, mammalian PLDs also require PIP2 as an essential cofactor for their enzymatic activity [102]. PLD is present in Golgi membranes [103] and it hydrolyzes PC to PA, a downstream effector of the small guanosine triphosphate (GTP)-binding protein ademine diphosphate (ADP)-ribosylation factor (ARF-1) [104]. Finally, PA can also be converted to DAG by PA phosphatases, whose activity is involved in both lipid metabolism and glycerolipid signalling [105]. The complexity of the signalling and metabolic pathways in which phospholipids participate, as well as the cross-talk between these cascades, emphasizes the existence of highly sophisticated regulatory mechanisms that remain to be fully understood. Together, these studies demonstrate the role of membrane lipids in a large variety of cellular functions and emphasize the close relationship between membrane lipid composition and function. In addition, the number of existing human pathologies related to alterations in lipid metabolism is evidence of the importance of membrane lipids and their role in signalling pathways (Table 3).


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)

Phospholipase cascade of PLD activation and amplification of diacylglycerol production. Abbreviations: PI-PLC, phosphatidylinositol-specific phospholipase C; DG, diacylglyerol; PC, phosphatidylcholine; PA, phosphatidic acid; PKC, protein kinase C; PIP2, PI-4,5-bisphosphate and PIP kinase, PI phosphate kinase. Adapted from [100].
© Copyright Policy
Related In: Results  -  Collection

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

fig06: Phospholipase cascade of PLD activation and amplification of diacylglycerol production. Abbreviations: PI-PLC, phosphatidylinositol-specific phospholipase C; DG, diacylglyerol; PC, phosphatidylcholine; PA, phosphatidic acid; PKC, protein kinase C; PIP2, PI-4,5-bisphosphate and PIP kinase, PI phosphate kinase. Adapted from [100].
Mentions: An additional degree of complexity in membrane lipid functions lies in the metabolic relationship between phospholipid species. There is a relatively large number of phospholipases and phosphatases that specifically participate in the interconversion of phospholipids and that in turn, can modulate the activity of those enzymes. The cascade of phospholipase D (PLD) activation is a clear example of this complexity (Fig. 6) [100]. The initial step of the cascade involves the agonist-induced and GPCR-mediated activation of phospholipase C (PLC) to hydrolyze phosphatidylinositol (PIP2) into DAG and IP3. The former activates PKC and the latter induces the release of Ca2+ into the cytosol through IP3-activated channels, which also activates PKC [101]. Interestingly, mammalian PLDs also require PIP2 as an essential cofactor for their enzymatic activity [102]. PLD is present in Golgi membranes [103] and it hydrolyzes PC to PA, a downstream effector of the small guanosine triphosphate (GTP)-binding protein ademine diphosphate (ADP)-ribosylation factor (ARF-1) [104]. Finally, PA can also be converted to DAG by PA phosphatases, whose activity is involved in both lipid metabolism and glycerolipid signalling [105]. The complexity of the signalling and metabolic pathways in which phospholipids participate, as well as the cross-talk between these cascades, emphasizes the existence of highly sophisticated regulatory mechanisms that remain to be fully understood. Together, these studies demonstrate the role of membrane lipids in a large variety of cellular functions and emphasize the close relationship between membrane lipid composition and function. In addition, the number of existing human pathologies related to alterations in lipid metabolism is evidence of the importance of membrane lipids and their role in signalling pathways (Table 3).

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