Sometimes, however, there are drawbacks to the stringent quality-control mechanism. The predominant mutations that cause cystic fibrosis, a common inherited disease, result in the production of a slightly misfolded form of a plasma membrane protein important for Cl– transport. Although the mutant protein would function normally if it reached the plasma membrane, it is retained in the ER and then is degraded by cytosolic proteasomes. This devastating disease thus results not because the mutation inactivates the protein but because the active protein is discarded before it reaches the plasma membrane.
vesicular Tubular clusters Mediate Transport from the er to the golgi apparatus
After transport vesicles have budded from ER exit sites and have shed their coat, they begin to fuse with one another. The fusion of membranes from the same compartment is called homotypic fusion, to distinguish it from heterotypic fusion, in which a membrane from one compartment fuses with the membrane of a different compartment. As with heterotypic fusion, homotypic fusion requires a set of matching SNAREs. In this case, however, the interaction is symmetrical, with both membranes contributing v-SNAREs and t-SNAREs (Figure 13–23).
The structures formed when ER-derived vesicles fuse with one another are called vesicular tubular clusters, because they have a convoluted appearance in
Figure 13–23 Homotypic membrane fusion. In step 1, nsf pries apart identical pairs of v-snares and t-snares in both membranes (see figure 13–20). In steps 2 and 3, the separated matching snares on adjacent identical membranes interact, which leads to membrane fusion and the formation of one continuous compartment. subsequently, the compartment grows by further homotypic fusion with vesicles from the same kind of membrane, displaying matching snares. homotypic fusion occurs when er-derived transport vesicles fuse with one another, but also when endosomes fuse to generate larger endosomes. rab proteins help regulate the extent of homotypic fusion and hence the size of a cell’s compartments (not shown).
Figure 13–24 Vesicular tubular clusters. (a) an electron micrograph of vesicular tubular clusters forming around an exit site. Many of the vesicle-like structures seen in the micrograph are cross sections of tubules that extend above and below the plane of this thin section and are interconnected. (b) vesicular tubular clusters move along microtubules to carry proteins from the
ER er to the golgi apparatus. copI-coated vesicles mediate the budding of vesicles that return to the (A) 0.2 µm er from these clusters (and from the golgi apparatus). (a, courtesy of william balch.) the electron microscope (Figure 13–24A). These clusters constitute a compartment that is separate from the ER and lacks many of the proteins that function in the ER. They are generated continually and function as transport containers that bring material from the ER to the Golgi apparatus. The clusters move quickly along microtubules to the Golgi apparatus with which they fuse (Figure 13–24B and Movie 13.2).
As soon as vesicular tubular clusters form, they begin to bud off transport vesicles of their own. Unlike the COPII-coated vesicles that bud from the ER, these vesicles are COPI-coated (see Figure 13–24A). COPI-coated vesicles are unique in that the components that make up the inner and outer coat layers are recruited as a preassembled complex, called coatomer. They function as a retrieval pathway, carrying back ER resident proteins that have escaped, as well as proteins such as cargo receptors and SNAREs that participated in the ER budding and vesicle fusion reactions. This retrieval process demonstrates the exquisite control mechanisms that regulate coat assembly reactions. The COPI coat assembly begins only seconds after the COPII coats have been shed, and remains a mystery how this switch in coat assembly is controlled.