The Retrieval Pathway to the ER Uses Sorting Signals
The retrieval pathway for returning escaped proteins back to the ER depends on ER retrieval signals. Resident ER membrane proteins, for example, contain signals that bind directly to COPI coats and are thus packaged into COPI-coated transport vesicles for retrograde delivery to the ER. The best-characterized signal of this type consists of two lysines, followed by any two other amino acids, at the extreme C-terminal end of the ER membrane protein. It is called a KKXX sequence, based on the single-letter amino acid code.
Soluble ER resident proteins, such as BiP, also contain a short retrieval signal at their C-terminal end, but it is different: it consists of a Lys-Asp-Glu-Leu or similar sequence. If this signal (called the KDEL sequence) is removed from BiP by genetic engineering, the protein is slowly secreted from the cell. If the signal is transferred to a protein that is normally secreted, the protein is now efficiently returned to the ER, where it accumulates.
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Unlike the retrieval signals on ER membrane proteins that can interact directly with the COPI coat, soluble ER resident proteins must bind to specialized receptor proteins such as the KDEL receptor—a multipass transmembrane protein that binds to the KDEL sequence and packages any protein displaying it into COPI-coated retrograde transport vesicles. To accomplish this task, the KDEL receptor itself must cycle between the ER and the Golgi apparatus, and its affinity for the KDEL sequence must be different in these two compartments. The receptor must have a high affinity for the KDEL sequence in vesicular tubular clusters and the Golgi apparatus, so as to capture escaped ER resident proteins that are present there at low concentration. It must have a low affinity for the KDEL sequence in the ER, however, to unload its cargo in spite of the very high concentration of KDEL-containing resident proteins in the ER.
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How can the affinity of the KDEL receptor change depending on the compartment in which it resides? The answer may be related to the different pH values established in the different compartments, regulated by H+ pumps in their membrane. The KDEL receptor could bind the KDEL sequence under the slightly acidic conditions in vesicular tubular clusters and the Golgi compartment but release it at the neutral pH in the ER. As we discuss later, such pH-sensitive protein-protein interactions form the basis for many of the sorting steps in the cell (Figure 13-21).
Most membrane proteins that function at the interface between the ER and Golgi apparatus, including v- and t-SNARES and some cargo receptors, enter the retrieval pathway to the ER. Whereas the recycling of some of these proteins is signal-mediated as just described, for others no specific signal seems to be required. Thus, while retrieval signals increase the efficiency of the retrieval process, some proteins—including some Golgi enzymes—randomly enter budding vesicles destined for the ER and are returned to the ER at a slower rate. Such Golgi enzymes cycle constantly between the ER and the Golgi, but their rate of return to the ER is slow enough for most of the protein to be found in the Golgi apparatus.
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