D C

Integral proteins play a role in many other cellular processes. They serve as transporters and ion channels (discussed in Section 11.3) and as receptors for hormones, neurotransmitters, and growth factors (Chapter 12). They are central to oxidative phosphorylation and photosynthesis (Chapter 19) and to cell-cell and antigen-cell recognition in the immune system (Chapter 5). Integral proteins are also important players in the membrane fusion that accompanies exocytosis, en-docytosis, and the entry of many types of viruses into host cells.

Membrane Fusion Is Central to Many Biological Processes

A remarkable feature of the biological membrane is its ability to undergo fusion with another membrane without losing its continuity. Although membranes are stable, they are by no means static. Within the eukaryotic endomembrane system (which includes the nuclear membrane, endoplasmic reticulum, Golgi, and various small vesicles), the membranous compartments constantly reorganize. Vesicles bud from the endoplasmic reticulum to carry newly synthesized lipids and proteins to other organelles and to the plasma membrane. Exo-cytosis, endocytosis, cell division, fusion of egg and sperm cells, and entry of a membrane-enveloped virus into its host cell all involve membrane reorganization in which the fundamental operation is fusion of two membrane segments without loss of continuity (Fig. 11-23).

Specific fusion of two membranes requires that (1) they recognize each other; (2) their surfaces become closely apposed, which requires the removal of water molecules normally associated with the polar head groups of lipids; (3) their bilayer structures become locally disrupted, resulting in fusion of the outer leaflet of each membrane (hemifusion); and (4) their bilayers fuse to form a single continuous bilayer. Receptor mediated en-docytosis, or regulated secretion, also requires that (5) the fusion process is triggered at the appropriate time or in response to a specific signal. Integral proteins called fusion proteins mediate these events, bringing about specific recognition and a transient local distortion of the bilayer structure that favors membrane fusion. (Note that these fusion proteins are unrelated to the products of two fused genes, also called fusion proteins, discussed in Chapter 9.)

Two cases of membrane fusion are especially well studied: the entry into a host cell of an enveloped virus such as influenza virus, and the release of neurotrans-mitters by exocytosis. Both processes involve complexes of fusion proteins that undergo dramatic confor-mational changes.

The influenza virus is surrounded by a membrane containing, among other proteins, many molecules of the hemagglutination (HA) protein (named for its abil-

FIGURE 11-23 Membrane fusion. The fusion of two membranes is central to a variety of cellular processes involving both organelles and the plasma membrane.

ity to cause erythrocytes to clump together). The virus enters a host cell by inducing endocytosis, which encloses the virus in an endosome, a small membrane vesicle with a pH of about 5 (Fig. 11-24). At this pH, a conformational change in the HA protein occurs, exposing a sequence within the HA protein called the fusion peptide and enabling the protein to penetrate the endosomal membrane. The endosomal membrane and the viral membrane are now connected through the HA protein. Next, the HA protein bends at its middle to form a hairpin shape, bringing its two ends together. This pulls the two membranes into close apposition and causes fusion of the viral membrane and the endosomal membrane. The HA protein functions as a trimer (Fig. 11-24). In its low-pH form, three HA domains at the closed end of the hairpin twist about each other to form a stable, coiled structure. The fusion process involves an intermediate stage (hemifusion) in which the outer leaflet of the viral membrane is fused with the inner leaflet of the endosomal membrane, while the other two leaflets maintain their continuity. At the point of hemi-fusion, the lipid bilayer must be temporarily disorganized, presumably caused by the HA fusion peptide

Cytosol

Secretory vesicle

Neurotransmitter-filled vesicle approaches plasma membrane.

Virus

Virus binds sialic acid receptors on host surface.

Virus

Virus triggers endocytosis; becomes enclosed in an endosome.

HA protein in pH 7 form has fusion peptides buried.

Neurotransmitter molecules v-SNARE

t-SNARE

Plasma membrane v-SNARE and t-SNARE bind to each other, zipping up from the amino termini and drawing the two membranes together.

Neurotransmitter molecules v-SNARE

t-SNARE

Plasma membrane v-SNARE and t-SNARE bind to each other, zipping up from the amino termini and drawing the two membranes together.

HA protein (trimer)

Low pH of endosome triggers extension of HA fusion peptides, which insert into endosomal membrane.

Fusion peptide

HA folds into hairpins, drawing viral and endosomal membranes together.

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