Membrane Dynamics:- 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 mem brane 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 endocytosis, 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 neurotransmitters by exocytosis. Both processes involve complexes of fusion proteins that undergo dramatic conformational changes. The influenza virus is surrounded by a membrane containing, among other proteins, many molecules of the hemagglutination (HA) protein (named for its ability to cause erythrocytes to clump together). The virus enters a host cell by inducing endocytosis, which en closes 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, ex posing 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

FIGURE 11–24 Fusion induced by the hemagglutinin (HA) protein during viral infection. HA protein is exposed on the membrane sur face of the influenza virus. When the virus moves from the neutral pH of the interstitial fluid to the low-pH compartment (endosome) in the host cell, HA undergoes dramatic shape changes that mediate fusion of the viral and endosomal membranes, releasing the viral contents into the cytoplasm.

FIGURE 11–25 Fusion during neurotransmitter release at a synapse. The membrane of the secretory vesicle contains the v-SNARE synap tobrevin (red). The target (plasma) membrane contains the t-SNAREs syntaxin (blue) and SNAP25 (violet). When a local increase in [Ca²⁺] signals release of neurotransmitter, the v-SNARE, SNAP25, and t-SNARE interact, forming a coiled bundle of four helices, pulling the two membranes together and disrupting the bilayer locally, which leads to membrane fusion and neurotransmitter release.

domains. Complete fusion results in release of the viral contents into the host cell cytoplasm. Neurotransmitters are released at synapses when intracellular vesicles loaded with neurotransmitter fuse with the plasma membrane. This process involves a family of proteins called SNARES (Fig. 11–25). SNAREs in the cytoplasmic face of the intracellular vesicles are called v-SNAREs; those in the target membranes with which the vesicles fuse (the plasma membrane during exocytosis) are t-SNAREs. Two other proteins, SNAP25 and NSF, are also involved. During fusion, v- and t-SNAREs bind to each other and undergo a structural change that produces a bundle of long thin rods made up of helices from both v- and t-SNARES and two helices from SNAP25 (Fig. 11–25). The two SNAREs initially interact at their ends, then zip up into the bundle of helices. This structural change pulls the two membranes into contact and initiates the fusion of their lipid bilayers. The complex of SNAREs and SNAP25 is the target of the powerful Clostridium botulinumtoxin, a pro tease that cleaves specific bonds in these proteins, pre venting neurotransmission and causing the death of the organism. Because of its very high specificity for these proteins, purified botulinum toxin has served as a powerful tool for dissecting the mechanism of neurotransmitter release in vivo and in vitro.

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مواضيع ذات صلة

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The Composition and Architecture of Membranes:- Peripheral Membrane Proteins Are Easily Solubilized

The Composition and Architecture of Membranes:- A Lipid Bilayer Is the Basic Structural Element of Membranes

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Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Hemoglobin Undergoes a Structural Change on Binding Oxygen

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Hemoglobin Subunits Are Structurally Similar to Myoglobin

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Oxygen Is Transported in Blood by Hemoglobin

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Protein Structure Affects How Ligands Bind

Membrane Dynamics:- Transbilayer Movement of Lipids Requires Catalysis

The Composition and Architecture of Membranes:- Lipids and Proteins Diffuse Laterally in the Bilayer