Membranes amphipathic

The lipids found in biological systems are either hydrophobic (containing only nonpolar groups) or amphipathic, which means they possess both polar and nonpolar groups. The hydrophobic nature of lipid molecules allows membranes to act as effective barriers to more polar molecules. In this chapter, we discuss the chemical and physical properties of the various classes of lipid molecules. The following chapter considers membranes, whose properties depend intimately on their lipid constituents. 

FIGURE 10.31 The umbrella model of membrane chamiel protein insertion. Hydrophobic helices insert directly into the core of the membrane, with amphipathic helices arrayed on the surface like an open umbrella. A trigger signal (low pH or a voltage gradient) draws some of the amphipathic helices into and across the membrane, causing the pore to open. 

CTC, used extensively to monitor calcium release in both whole cells and isolated organelles (28-33), is an amphipathic molecule that easily passes through cell membranes (see Figure 1). The fluorescence of this probe is enhanced more than fiftyfold by binding of calcium when the dye is intercalated into biological membranes. 

Uncouplers (eg, dinitrophenol) are amphipathic (Chapter 14) and increase the petmeabihty of the lipoid inner mitochondrial membrane to protons (Figure 12—8), thus teducing the electtochemical potential and shott-citcuiting the ATP synthase. In this way, oxidation can proceed without phosphotylation. 

Lipids have the common property of being relatively insoluble in water (hydrophobic) but soluble in nonpolar solvents. Amphipathic lipids also contain one or more polar groups, making them suitable as constituents of membranes at lipidiwater interfaces. 

Cholesterol, an amphipathic lipid, is an important component of membranes. It is the parent molecule from which all other steroids in the body, including major hormones such as the adrenocortical and sex hormones, D vitamins, and bile acids, are synthesized. 

Triacylglycerols are the major energy-storing lipids, whereas phosphoglycerols, sphingomyelin, and gly-cosphingolipids are amphipathic and have structural functions in cell membranes as well as other specialized roles. 

The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules (Figure 25-1). These are oriented so that their polar groups face outward to the aqueous medium, as in the cell membrane (Chapter 14). The protein moiety of a lipoprotein is known as an apo-lipoprotein or apoprotein, constituting nearly 70% of some HDL and as litde as 1% of chylomicrons. Some apolipoproteins are integral and cannot be removed, whereas others are free to transfer to other hpoproteins. 

The amphipathic character of phospholipids suggests that the two regions of the molecule have incompatible solubihties however, in a solvent such as water, phos-phohpids organize themselves into a form that thermodynamically serves the solubihty requirements of both regions. A micelle (Figure 41 ) is such a structure the hydrophobic regions are shielded from water, while the hydrophilic polar groups are immersed in the aqueous environment. However, micelles are usually relatively small in size (eg, approximately 200 nm) and thus are hmited in their potential to form membranes. 

The hydrophobic C domain appears to start with an amphipathic membrane-spanning helix [5]. 

Fig. 1. Hypothetical secondary structure of a human plasma membrane Na /H exchanger. (Adapted from Sardet et al. [53].) Shaded bars, putative transmembrane segments. Hatched bars, putative amphipathic helices (numbers at tops and bottoms of bars refer to positions of amino acids). CHO, possible site of N-linked glycosylation. Solid bars, regions of the porcine renal Na /H exchanger used for immunolocalization in LLC-PK cells.

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. 

FIGURE 2.1 A side view of the structure of the prototype G-protein-coupled, 7TM receptor rhodopsin. The x-ray structure of bovine rhodopsin is shown with horizontal gray lines, indicating the limits of the cellular lipid membrane. The retinal ligand is shown in a space-filling model as the cloud in the middle of the structure. The seven transmembrane (7TM) helices are shown in solid ribbon form. Note that TM-III is rather tilted (see TM-III at the extracellular and intracellular end of the helix) and that kinks are present in several of the other helices, such as TM-V (to the left), TM-VI (in front of the retinal), and TM-VII. In all of these cases, these kinks are due to the presence of a well-conserved proline residue, which creates a weak point in the helical structure. These kinks are believed to be of functional importance in the activation mechanism for 7TM receptors in general. Also note the amphipathic helix-VIII which is located parallel to the membrane at the membrane interface. 

In the x-ray structure of rhodopsin, an amphipathic helix runs parallel to the membrane from the intracellular end of TM-VII beneath the seven-helical bundle to the other side of TM-I and TM-II. At this point, one or more Cys residues are often found and are known to be subject to a dynamic posttranslational modification with palmitic acid residues. Like the phosphorylation event, the palmitoylation process appears to be dynamically regulated by receptor occupancy and is also involved in the desensitization phenomenon. The two posttranslational modifications can influence each other. For example, the conformational constraint induced by palmitoylation may alter the accessibility of certain phosphorylation sites. Like the phosphorylation process, the functional consequences of palmitoylation also appear to vary from receptor to receptor. 

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