Membrane lipid bilayers features

Proposed features of the interaction between the prothrombinase complex and a membrane lipid bilayer.Ky and K2 are the kringle domains of prothrombin, and EGFl and EGF2 are the two epidermal growth factor units of factor X. Prothrombin and factor form a heterodimer complex harbored within the membrane protein factor Va- The proposed interaction between prothrombin and factor X involves hydrophobic interactions between two helices and bridging by a ion between two Gla residues. The N-terminal Gla residues attach the heterodimer complex to the phospholipid surface. Figure kindly provided by C. C. F. Blake. 

The structural features that determine the pharmacophoric segment of sartans have also been examined by combination of quantitative structure-activity relationship (QSAR) and conformational analysis. The results show that the site of action for sartans as ATI antagonists include amino acids Lysl99, VallOS and His256 located in the mesophase of membrane lipid bilayers [14],... 

While the fluid mosaic model of membrane stmcture has stood up well to detailed scrutiny, additional features of membrane structure and function are constantly emerging. Two structures of particular current interest, located in surface membranes, are tipid rafts and caveolae. The former are dynamic areas of the exo-plasmic leaflet of the lipid bilayer enriched in cholesterol and sphingolipids they are involved in signal transduction and possibly other processes. Caveolae may derive from lipid rafts. Many if not all of them contain the protein caveolin-1, which may be involved in their formation from rafts. Caveolae are observable by electron microscopy as flask-shaped indentations of the cell membrane. Proteins detected in caveolae include various components of the signal-transduction system (eg, the insutin receptor and some G proteins), the folate receptor, and endothetial nitric oxide synthase (eNOS). Caveolae and lipid rafts are active areas of research, and ideas concerning them and their possible roles in various diseases are rapidly evolving. 

Dynamic aspects of drugs delivered into lipid bilayer membranes are significant in discussing bioactivities and the mechanism of the drug-membrane interactions. So far, however, the dynamic properties of drugs in the membrane interior have not been well understood. No systematic NMR experiments have been carried out because of the low concentration of the bilayer interior. In this section, we illustrate how to obtain dynamic features of drug molecules trapped in membranes by NMR. 

Amphipathic peptides contain amino acid sequences that allow them to adopt membrane active conformations [219]. Usually amphipathic peptides contain a sequence with both hydrophobic amino acids (e.g., isoleucine, valine) and hydrophilic amino acids (e.g., glutamic acid, aspartic acid). These sequences allow the peptide to interact with lipid bilayer. Depending on the peptide sequence these peptides may form a-helix or j6-sheet conformation [219]. They may also interact with different parts of the bilayer. Importantly, these interactions result in a leaky lipid bilayer and, therefore, these features are quite interesting for drug delivery application. Obviously, many of these peptides are toxic due to their strong membrane interactions. 

We have encountered examples of simple lipid bilayers earlier. These bilayers are composed largely of amphipathic molecules. In water, they have their hydrophobic parts occupying the center of the bilayer and their hydrophilic parts occupying the bilayer surface. Such bilayers form a continuous and essential structural feature of virtually all biological membranes. We need to distinguish between that layer which faces out from the cell and is in contact with the external environment, the exoplasmic leaflet, and that which faces in and is in contact with the cellular contents, the cytoplasmic leaflet. As we shall see, these two aspects of the lipid bilayer are quite distinct. 

A. The main structural feature of biologic membranes is the lipid bilayer (Figure... 

Membranes are composed of lipids and proteins in varying combinations particular to each species, cell type, and organelle. The fluid mosaic model describes features common to all biological membranes. The lipid bilayer is the basic structural unit. Fatty acyl chains of phospholipids and the steroid nucleus of sterols are oriented toward the interior of the bilayer their hydrophobic interactions stabilize the bilayer but give it flexibility. 

Although numerous models for the structure of membranes have been proposed, the structural features which are generally accepted at present are rather similar to the original Danielli-Davson model. There is convincing evidence that the structure is dominated by lipid bilayers. The state of order of the hydrocarbon chains is now being studied extensively by many groups (see below). Less is known about the proteins. Besides the proteins that are located on the outside according to the Danielli-Davson model, there are also proteins that are partly buried in the hydro-phobic interior of the lipid layer however, little is known about the lipid-protein interaction. 

From the earliest description of the toxin s actions on neuronal systems, it emerged that a-LTX affects specifically the presynaptic element, from which it causes massive neurotransmitter release (e.g., Longenecker et al. 1970). The toxin has no major enzymatic activities (Frontali et al. 1976). Crucially, a-LTX has been discovered to create Ca2+-permeable channels in lipid bilayers (Finkelstein et al. 1976), and a large body of evidence shows that Ca2+ influx through membrane channels induced by a-LTX in the presynaptic membrane accounts for a major part of its effect. Pore formation occurs in all the biological systems mentioned above, but the features of a-LTX-triggered release cannot be fully explained by the toxin pore. 

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