The ER is an extensive membranous network that is continuous with the outer nuclear membrane and is the site for the synthesis of the massive amounts of lipids and proteins used to build the plasma membrane and the membranes of most cellular organelles. The ER comprises three interconnected domains: rough ER, smooth ER, and ER exit sites. The rough ER, abundant in cells specialized in protein secretion, such as cells of exocrine glands or plasma cells, is studded with bound ribosomes that are actively synthesizing proteins. The smooth ER lacks ribosomes, is not very abundant in most cells (except hepatocytes), and is thought to be the site of lipid biosynthesis and of cytochrome P450–mediated detoxification reactions. ER exit sites are specialized areas of the ER membrane where transport cargo is packaged into transport vesicles enroute to the Golgi apparatus.

Nascent secretory proteins are marked for cotranslational translocation into the ER by the presence of an amino-terminal ER signal sequence  that contains one or more positively charged amino acids followed by a continuous stretch of 6 to 12 hydrophobic residues. As the signal sequence emerges from the ribosome, it is recognized by the signal recognition particle (SRP), a ribonucleoprotein, that docks the ribosome to the ER membrane by interaction with the SRP receptor. Upon binding of GTP to the SRP and its receptor, the ribosome and the nascent chain are transferred in close proximity to the Sec61 translocon complex on the cytosolic face of the ER mem brane. As the nascent polypeptide emerges from the luminal side of the translocon in an N-to-C direction, its signal sequence is cleaved by signal peptidase, translation is completed, and the protein assumes its folded configuration. Proteins without specific targeting sequences fully enter the ER lumen. For proteins destined to membranes, trans membrane domains consisting of approximately 20 largely apolar amino acids anchor the protein to the ER membrane lipid bilayer.

From the ER, proteins are transported to the plasma membrane and secreted or integrated into the membrane or targeted to endosomes; alternatively they are transported to the Golgi, lysosomes, and other organelles or retained in the ER as their final destination.[1] Transport through the secretory pathway is mediated by vesicles, and sorting motifs within proteins dictate the selective incorporation of cargo proteins into vesicles and their delivery to the intended destination.

On achieving transport competence, proteins are granted access to higher-ordered membrane domains termed ER exit sites. At ER exit sites, membrane-bound and soluble proteins are concentrated into transport vesicles for trafficking to a network of smooth membranes called the ER-Golgi intermediate compartment (ERGIC). COPII complex, composed of coat proteins, concentrates and packages the protein cargo into vesicles. COPII binds to cargo molecules either directly, if they span the membrane, or through intermediate cargo receptors and then provides some of the force that causes vesicle bud ding, thereby linking cargo acquisition to vesiculation.

ER-resident proteins are selectively sequestered in the ER, both for the absence of export signals and to the presence of ER retention signals. Soluble luminal ER resident proteins are retained through a C-terminal ER tetrapeptide retention motif KDEL. Frequently, transmembrane proteins have either a C-terminal dilysine motif KKXX or an Nt diarginine motif XXRR, or variants thereof for transmembrane proteins. However, it is more accurate to indicate ER localization signals as “retrieval motifs” because proteins bearing these signals can transiently escape from the ER into the ERGIC, from which they are returned to the ER through the retrograde vesicular transport.

For the KDEL motif of luminal ER proteins, a specific retrieval receptor has been identified, first in yeast and then in mammals. The KKXX motif has been shown to interact directly with the COPI coat protein complex that is involved in retrograde transport from the ER to the Golgi. Retrograde transport also serves to replenish the vesicle components lost as a result of anterograde (forward) transport. In conclusion, selective protein exit from the ER is achieved by monitoring/regulating (1) transport competence of nascent proteins, (2) capture of cargo in transport vesicles, and (3) protein retention/retrieval for ER-localized proteins.

References

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[1] Dancourt J, Barlowe C. Protein sorting receptors in the early secretory pathway. Annu Rev Biochem. 2010;79:777–802.

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Intra-Golgi Transport and Protein Processing

The Isolation and Structure of Operator

The Migration Retardation Assay and DNA Looping

Repressor Binds to DNA: The Operator is DNA

Detection and Purification of lac Repressor

The Difficulty of Detecting Wild-Type lac Repressor

An Assay for lac Repressor

Proving lac Repressor is a Protein

The Role of Inducer Analogs in the Study of the lac Operon

Background of the lac Operon

Mutagenesis with Chemically Synthesized DNA