To initiate their journey along the secretory pathway, proteins that have entered the ER and are destined for the Golgi apparatus or beyond are first packaged into COPII-coated transport vesicles. These vesicles bud from specialized regions of the ER called ER exit sites, whose membrane lacks bound ribosomes. Most animal cells have ER exit sites dispersed throughout the ER network.
Entry into vesicles that leave the ER can be a selective process or can happen by default. Many membrane proteins are actively recruited into such vesicles, where they become concentrated. These cargo membrane proteins display exit (transport) signals on their cytosolic surface that adaptor proteins of the inner COPII coat recognize (Figure 13–22); some of these components act as cargo receptors and are recycled back to the ER after they have delivered their cargo to the Golgi apparatus. Soluble cargo proteins in the ER lumen, by contrast, have exit signals that attach them to transmembrane cargo receptors. Proteins without exit signals can also enter transport vesicles, including protein molecules that normally function in the ER (so-called ER resident proteins), some of which slowly leak out of the ER and are delivered to the Golgi apparatus. Different cargo proteins enter the transport vesicles with substantially different rates and efficiencies, which may result from differences in their folding and oligomerization efficiencies and kinetics, as well as the factors already discussed. The exit step from the ER is a major checkpoint at which quality control is exerted on the proteins that a cell secretes or displays on its surface, as we discussed in Chapter 12.
The exit signals that direct soluble proteins out of the ER for transport to the Golgi apparatus and beyond are not well understood. Some transmembrane proteins that serve as cargo receptors for packaging some secretory proteins into COPII-coated vesicles are lectins that bind to oligosaccharides on the secreted
Figure 13–22 The recruitment of membrane and soluble cargo molecules into ER transport vesicles. Membrane proteins are packaged into budding transport vesicles through interactions of exit signals on their cytosolic tails with adaptor proteins of the inner copII coat. some of these membrane proteins function as cargo receptors, binding soluble proteins in the er lumen and helping to package them into vesicles. other proteins may enter the vesicle by bulk flow. a typical 50 nm transport vesicle contains about 200 membrane proteins, which can be of many different types. as indicated, unfolded or incompletely assembled proteins are bound to chaperones and transiently retained in the er compartment.
proteins. One such lectin, for example, binds to mannose on two secreted blood-clotting factors (Factor V and Factor VIII), thereby packaging the proteins into transport vesicles in the ER; its role in protein transport was identified because humans who lack it owing to an inherited mutation have lowered serum levels of Factors V and VIII, and they therefore bleed excessively.
only proteins That are properly folded and assembled can leave the er
To exit from the ER, proteins must be properly folded and, if they are subunits of multiprotein complexes, they need to be completely assembled. Those that are misfolded or incompletely assembled transiently remain in the ER, where they are bound to chaperone proteins (discussed in Chapter 6) such as BiP or calnexin. The chaperones may cover up the exit signals or somehow anchor the proteins in the ER. Such failed proteins are eventually transported back into the cytosol, where they are degraded by proteasomes (discussed in Chapters 6 and 12). This quality-control step prevents the onward transport of misfolded or misassembled proteins that could potentially interfere with the functions of normal proteins. Such failures are surprisingly common. More than 90% of the newly synthesized subunits of the T cell receptor (discussed in Chapter 24) and of the acetylcholine receptor (discussed in Chapter 11), for example, are normally degraded without ever reaching the cell surface where they function. Thus, cells must make a large excess of some protein molecules to produce a select few that fold, assemble, and function properly.