Band 4.1 protein; ezrin, radixin, moesin (ERM)^

PIP2, PIP3, and PI-3P = phosphatidylinositol derivatives with additional phosphate groups on the inositol ring (see Figure 14-26); PH = pleckstrin homology; PS = phosphatidylserine;.

^ These proteins have roles in linking the actin cytoskeleton to the plasma membrane.

mechanism by which peripheral proteins were bound to membranes. The results of more recent research indicate that protein-lipid interactions are equally important in localizing peripheral proteins to cellular membranes (see Figure 5-11).

Analyses of genome sequences have revealed several widely distributed lipid-binding motifs in proteins (Table 5-3). For instance, the pleckstrin homology (PH) domain, which binds two types of phosphorylated phosphatidyli-nositols, is the eleventh most common protein domain encoded in the human genome. This domain was initially recognized in pleckstrin, a protein found in platelets. The high frequency of the PH domain indicates that proteins localized to membrane surfaces carry out many important functions. Other common lipid-binding motifs include the C2 domain, the ankyrin-repeat domain, and the FERM domain. Originally discovered in protein kinase C, the C2 domain is a membrane-targeting domain for various kinases, phosphatases, and phospholipases.

The phospholipases are representative of those water-soluble enzymes that associate with the polar head groups of membrane phospholipids to carry out their catalytic functions. As noted earlier, phospholipases hydrolyze various bonds in the head groups of phospholipids (see Figure 5-9). These enzymes have an important role in the degradation of damaged or aged cell membranes and are active molecules in many snake venoms. The mechanism of action of phospholipase A2 illustrates how such water-soluble enzymes can reversibly interact with membranes and catalyze reactions at the interface of an aqueous solution and lipid surface. When this enzyme is in aqueous solution, its Ca2+-containing active site is buried in a channel lined with hy-drophobic amino acids. The enzyme binds with greatest affinity to bilayers composed of negatively charged phos-pholipids (e.g., phosphotidylethanolamine). This finding suggests that a rim of positively charged lysine and arginine residues around the entrance catalytic channel is particularly important in interfacial binding (Figure 5-17a). Binding

▲ FIGURE 5-17 Interfacial binding surface and mechanism of action of phospholipase A2. (a) A structural model of the enzyme showing the surface that Interacts with a membrane. This Interfacial binding surface contains a rim of positively charged arginine and lysine residues shown in blue surrounding the cavity of the catalytic active site in which a substrate lipid (red stick structure) is bound. (b) Diagram of catalysis by phospholipase A2. When docked on a model lipid membrane, positively charged residues of the interfacial binding site bind to negatively charged polar groups at the membrane surface. This binding triggers a small conformational change, opening a channel lined with hydrophobic amino acids that leads from the bilayer to the catalytic site. As a phospholipid moves into the channel, an enzyme-bound Ca2+ ion (green) binds to the head group, positioning the ester bond to be cleaved next to the catalytic site. [Part (a) adapted from M. H. Gelb et al., 1999, Curr. Opin. Struc. Biol. 9:428. Part (b), see D. Blow, 1991, Nature 351:444.]

induces a small conformational change in phospholipase A2 that fixes the protein to the phospholipid heads and opens the hydrophobic channel. As a phospholipid molecule diffuses from the bilayer into the channel, the enzyme-bound Ca2+ binds to the phosphate in the head group, thereby positioning the ester bond to be cleaved next to the catalytic site (Figure 5-17b).

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