Lipids amphipathic helices

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. 

The top side of the helix contains only hydrophobic side chains, while the other surfaces are polar or charged this is an amphipathic helix. As an integral membrane protein, it is likely to dip its hydrophobic surface into the lipid bilayer but expose the other surfaces to the aqueous phase. An alternative arrangement might be to cluster, say, 10 helices, one from each of 10 subunits, around a central hydrophilic core, while exposing only the hydrophobic surface to the lipid bilayer. 

Fig. 2. A model for lipoprotein structure based on the interactions between apolipopro-teins and lipid constituents. The surface monolayer is composed of phospholipids and apolipoproteins. The apoproteins contain helical regions which are amphipathic. The hydrophobic surface of the amphipathic helix interacts with the fatty acyl chains of phospholipids, and the hydrophilic surface is exposed to the aqueous environment of the polar head groups and the plasma. Adapted from Pownall et al.. (1981).

The amphipathic helix, in which residues are spaced so that the helical periodicity places hydrophobic side chains on one side of the helix and hydrophilic side chains on the other, is a common structural motif used by the peripheral apolipoproteins to bind lipid (Segrest et al., 1992) it is also a structural element present in globular proteins (Perutz et al., 1965). 

Class A amphipathic helix I I Class G amphipathic helix 0 Hydrophobic moment/residue < b Lipid-binding firagment... 

Class Y amphipathic helix Non-lipid-binding fragment... 

A series of peptide analogs of class A and class L amphipathic helices were synthesized and studied (Tytler et ai, 1993). Two of these peptides, designated 18A and 18L, were modeled as idealized a helices, energy minimized, and displayed in cross section (Tytler etal., 1993). The overall cross-sectional shape of a class A amphipathic helix in the snorkel orientation was found to be that of a wedge with a polar base and a hydrophobic apex, schematically illustrated in Fig. 6A. In contrast, the shape of a class L amphipathic helix in cross section is reciprocal to that of a class A amphipathic helix i.e., an inverted wedge with its apex at the polar face and its base buried in the lipid (Fig. 6B). 

As shown in the amphipathic helix map (Fig. 7), the amino-terminal class G amphipathic helical domains of apoE, with a relatively weak lipid affinity (Gianturco et al., 1983), correspond closely to the position of a... 

The amphipathic helix map (Fig. 7) suggests a second and perhaps related possibility for the lipid association of the amino-terminal domain of apoE. The class A amphipathic helix located between residues 181-192 is disordered in the crystal structure (Wilson et al., 1991) but might associate with lipid when lipid is present this region has been shown to be less protease sensitive when the amino-terminal domain is lipid bound (RaW etal., 1986). 

In a study by the Baylor group (Sparrow et ai, 1981), lipid-associating peptides (LAPs), LAP-16, LAP-20, and LAP-24 (16, 20, and 24 amino acid residues long, respectively), were shown to associate with phospholipid. This investigation showed that peptide analogs of the amphipathic helix as short as 10 to 12 residues in length have the ability to interact with phospholipid (McLean a/., 1991). 

Correlation of Lipid Association xoith Amphipathic Helix Class... 

One role of the class Y amphipathic helices found in apoA-IV and apoA-I appears to be to serve as low-affinity lipid-associating domains. The snorkel hypothesis predicts that this class of amphipathic helix would not penetrate as deeply into phospholipid surfaces as would class A and thus would have lower lipid affinity. This prediction is supported by experimental evidence (based on Trp fluorescence blue shifts, ease of Trp fluorescence quenching, and liposomal leakage) that apoA-IV sits higher in a phospholipid monolayer than do the other exchangeable apolipoproteins that contain class A amphipathic helices (Weinberg and Jordan, 1990). 

The apoproteins are distinct physically, chemically, and immunochemically and have important roles in lipid transport and metabolism (Table 20-1). In keeping with their individual metabolic functions, they have specific structural domains. Amino acid substitutions or deletions in critical domains result in functional abnormalities. The apoproteins share a common structure in the form of an amphipathic helix, in which the amino acid residues have hydrophobic side chains on one face of the helix and hydrophilic polar residues on the other. The hydrophilic face is believed to interact with the polar head groups of the phospholipids, while the hydrophobic residues interact with their fatty acid portions. 

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