Harpers

528 / CHAPTER 47Additional constituents are found in many GPI structures;for example, that shown in Figure 47–1 containsan extra phosphorylethanolamine attached to the middleof the three Man moieties of the glycan and an extrafatty acid attached to GlcNH 2 . The functional significanceof these variations among structures is not understood.This type of linkage was first detected by the useof bacterial PI-specific phospholipase C (PI-PLC),which was found to release certain proteins from theplasma membrane of cells by splitting the bond indicatedin Figure 47–1. Examples of some proteins thatare anchored by this type of linkage are given in Table47–13. At least three possible functions of this type oflinkage have been suggested: (1) The GPI anchor mayallow greatly enhanced mobility of a protein in theplasma membrane compared with that observed for aprotein that contains transmembrane sequences. This isperhaps not surprising, as the GPI anchor is attachedonly to the outer leaflet of the lipid bilayer, so that it isfreer to diffuse than a protein anchored via both leafletsof the bilayer. Increased mobility may be important in facilitatingrapid responses to appropriate stimuli. (2) SomeGPI anchors may connect with signal transductionpathways. (3) It has been shown that GPI structures cantarget certain proteins to apical domains of the plasmamembrane of certain epithelial cells. The biosynthesis ofGPI anchors is complex and begins in the endoplasmicreticulum. The GPI anchor is assembled independentlyby a series of enzyme-catalyzed reactions and then transferredto the carboxyl terminal end of its acceptor protein,accompanied by cleavage of the preexisting carboxylterminal hydrophobic peptide from that protein.This process is sometimes called glypiation. An acquireddefect in an early stage of the biosynthesis of theGPI structure has been implicated in the causation ofparoxysmal nocturnal hemoglobinuria (see below).GLYCOPROTEINS ARE INVOLVEDIN MANY BIOLOGIC PROCESSES& IN MANY DISEASESAs listed in Table 47–1, glycoproteins have many differentfunctions; some have already been addressed inthis chapter and others are described elsewhere in thisTable 47–13. Some GPI-linked proteins.• Acetylcholinesterase (red cell membrane)• Alkaline phosphatase (intestinal, placental)• Decay-accelerating factor (red cell membrane)• 5′-Nucleotidase (T lymphocytes, other cells)• Thy-1 antigen (brain, T lymphocytes)• Variable surface glycoprotein (Trypanosoma brucei)text (eg, transport molecules, immunologic molecules,and hormones). Here, their involvement in two specificprocesses—fertilization and inflammation—will bebriefly described. In addition, the bases of a number ofdiseases that are due to abnormalities in the synthesisand degradation of glycoproteins will be summarized.Glycoproteins Are Importantin FertilizationTo reach the plasma membrane of an oocyte, a spermhas to traverse the zona pellucida (ZP), a thick, transparent,noncellular envelope that surrounds the oocyte.The zona pellucida contains three glycoproteins of interest,ZP1–3. Of particular note is ZP3, an O-linked glycoproteinthat functions as a receptor for the sperm. Aprotein on the sperm surface, possibly galactosyl transferase,interacts specifically with oligosaccharide chains ofZP3; in at least certain species (eg, the mouse), this interaction,by transmembrane signaling, induces the acrosomalreaction, in which enzymes such as proteases andhyaluronidase and other contents of the acrosome of thesperm are released. Liberation of these enzymes helpsthe sperm to pass through the zona pellucida and reachthe plasma membrane (PM) of the oocyte. In hamsters,it has been shown that another glycoprotein, PH-30, isimportant in both the binding of the PM of the sperm tothe PM of the oocyte and also in the subsequent fusionof the two membranes. These interactions enable thesperm to enter and thus fertilize the oocyte. It may bepossible to inhibit fertilization by developing drugs orantibodies that interfere with the normal functions ofZP3 and PH-30 and which would thus act as contraceptiveagents.Selectins Play Key Roles in Inflammation& in Lymphocyte HomingLeukocytes play important roles in many inflammatoryand immunologic phenomena. The first steps in manyof these phenomena are interactions between circulatingleukocytes and endothelial cells prior to passage ofthe former out of the circulation. Work done to identifyspecific molecules on the surfaces of the cells involvedin such interactions has revealed that leukocytesand endothelial cells contain on their surfaces specificlectins, called selectins, that participate in their intercellularadhesion. Features of the three major classes ofselectins are summarized in Table 47–14. Selectins aresingle-chain Ca 2+ -binding transmembrane proteins thatcontain a number of domains (Figure 47–10). Theiramino terminal ends contain the lectin domain, whichis involved in binding to specific carbohydrate ligands.The adhesion of neutrophils to endothelial cells ofpostcapillary venules can be considered to occur in four