Membrane fusion is the process by which a vesicle membrane incorporates its components into the target membrane and releases its cargo into the lumen of the organelle or, in the case of secretion, into the extracellular medium. Different steps in membrane fusion are distinguished. First, the vesicle and the target membrane mutually identify each other. Then, proteins from both membranes interact with one another to form stable complexes and bring the two membranes into close apposition, resulting in the docking of the vesicle to the target membrane. Finally, considerable energy needs to be supplied to force the membranes to fuse, since the low-energy organization—in which the hydrophobic tails of the phospholipids are kept away from water while the hydrophilic head groups are in an aqueous medium—must be disrupted, even if only briefly, as the vesicle and target membranes distort and then fuse.
Each type of vesicle must only dock with and fuse with the correct target membrane, otherwise the protein constituents of all the different organelles would become mixed with each other and with the plasma membrane. Our understanding of the molecular processes leading to membrane fusion is only just beginning to take shape, but our current understanding is that two types of proteins, called SNARES and Rab family GTPases work together to achieve this. SNARES located on the vesicles (v-SNARES) and on the target membranes (t-SNARES) interact to form a stable complex that holds the vesicle very close to the target membrane (Fig. 10.12). Not all vSNARES can interact with all tSNARES, so SNARES provide a first level of specificity. So far, over 50 members of the Rab family have been identified in mammalian cells, and each seems to be found at one particular site where it regulates one specific transport event, thus controlling which vesicle fuses with which target. For example, the recycling of the mannose-6-phosphate receptor back from the lysosome to the trans-Golgi network (Fig. 10.11) requires Rab9, and yellow fluorescent protein-Rab9 chimeras (page 150) locate to the returning vesicles. GTP hydrolysis by Rabs is thought to provide energy for membrane fusion.
Another important factor in membrane fusion is the lipid composition at the fusion site. In particular phosphoinositides, a group of lipids that we will encounter again in Chapter 16 (page 346), seem to play a crucial role.
complex formation very stable t-SNARES
complex formation very stable fusion and dissociation
Figure 10.12. SNAREs and vesicle fusion.
SNARES, Food Poisoning, and Face-Lifts
Botulism, food poisoning caused by a toxin released from the anaerobic bacterium Clostridium botulinum, is fortunately rare. Botulinum toxin comprises a number of enzymes that specifically destroy those SNARE proteins required for regulated exocytosis in nerve cells. Without these proteins regulated exocytosis cannot occur, so the nerve cells cannot tell muscle cells to contract. This causes paralysis: most critically, paralysis of the muscles that drive breathing. Death in victims of botulism results from respiratory failure.
Low concentrations of botulinum toxin (or "BoTox") can be injected close to muscles to paralyze them. For example, in a "chemical facelift," botulinum toxin is used to paralyze facial muscles, producing an effect variously described as "youthful" and "zombie-like."
1. The basic mechanisms of intracellular protein trafficking are similar in all eukaryotic cells, from yeast cells to human nerve cells.
2. The final destination of a protein is defined by sorting signals that are recognized by specific receptors. The polypeptide chain itself contains targeting sequences while glycosylation and phosphorylation can add additional sorting signals.
3. Some sorting signals activate translocation of a protein to a new location, while others such as the endoplasmic reticulum retention signal KDEL cause the protein to be retained at its present location.
4. Nuclear proteins are synthesized on free ribosomes and carried through the nuclear pore by Ran-mediated gated transport. Other proteins with a nuclear export signal are carried the other way, again by a Ran-mediated process.
5. Peroxisomal proteins, together with the majority of mitochondrial and chloroplast proteins that are not coded for by mitochondrial or chloroplast genes, are synthesized on free ribosomes and then transported across the membrane(s) of the target organelle.
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