![]() Free and membrane-bound ribosomes are functionally indistinguishable, and all protein synthesis initiates on ribosomes that are free in the cytosol. Ribosomes are targeted for binding to the ER membrane by the amino acid sequence of the polypeptide chain being synthesized, rather than by intrinsic properties of the ribosome itself. ![]() The first step in the cotranslational pathway is the association of ribosomes with the ER. In mammalian cells, most proteins enter the ER co-translationally, whereas both cotranslational and posttranslational pathways are used in yeast. Proteins can be translocated into the ER either during their synthesis on membrane-bound ribosomes (cotranslational translocation) or after their translation has been completed on free ribosomes in the cytosol (posttranslational translocation). Targeting Proteins to the Endoplasmic Reticulum In contrast, proteins destined to remain in the cytosol or to be incorporated into the nucleus, mitochondria, chloroplasts, or peroxisomes are synthesized on free ribosomes and released into the cytosol when their translation is complete. In mammalian cells, most proteins are transferred into the ER while they are being translated on membrane-bound ribosomes ( Figure 9.3). Proteins destined for secretion or incorporation into the ER, Golgi apparatus, lysosomes, or plasma membrane are initially targeted to the ER. The entrance of proteins into the ER thus represents a major branch point for the traffic of proteins within eukaryotic cells. Still other proteins travel through the initial steps of the secretory pathway but are then retained and function within either the ER or the Golgi apparatus. Plasma membrane and lysosomal proteins also travel from the rough ER to the Golgi and then to their final destinations. Further studies extended these results and demonstrated that this pathway is not restricted to proteins destined for secretion from the cell. These experiments defined a pathway taken by secreted proteins, the secretory pathway: rough ER → Golgi → secretory vesicles → cell exterior. Pancreatic acinar cells, which secrete most of their newly synthesized proteins into the digestive tract, were labeled with radioactive amino acids to study the intracellular pathway taken by secreted proteins. Following longer chase periods, the radiolabeled proteins traveled from the Golgi apparatus to the cell surface in secretory vesicles, which then fused with the plasma membrane to release their contents outside of the cell. If the cells were then incubated for a short time in media containing nonradioactive amino acids (a process known as a chase), the radiolabeled proteins were detected in the Golgi apparatus. After a brief exposure of pancreatic acinar cells to radioactive amino acids, newly synthesized proteins were detected in the rough ER, which was therefore identified as the site of synthesis of proteins destined for secretion. The location of the radiolabeled proteins within the cell was then determined by autoradiography, revealing the cellular sites involved in the events leading to protein secretion. Because most proteins synthesized by these cells are secreted, Palade and coworkers were able to study the pathway taken by secreted proteins simply by labeling newly synthesized proteins with radioactive amino acids. These investigators studied the fate of newly synthesized proteins in specialized cells of the pancreas (pancreatic acinar cells) that secrete digestive enzymes into the small intestine. The role of the endoplasmic reticulum in protein processing and sorting was first demonstrated by George Palade and his colleagues in the 1960s ( Figure 9.2). The Endoplasmic Reticulum and Protein Secretion
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