Outline

17.1 Techniques for Studying the Secretory Pathway

17.2 Molecular Mechanisms of Vesicular Traffic

17.3 Vesicle Trafficking in the Early Stages of the Secretory Pathway

17.4 Protein Sorting and Processing in Later Stages of the Secretory Pathway

17.5 Receptor-Mediated Endocytosis and the Sorting of Internalized Proteins

17.6 Synaptic Vesicle Function and Formation

Exterior

Regulated secretion

Trans-Golgi network

Sorting to lysosomes

Transport vesicle

Exterior

Sorting to lysosomes

Regulated secretion

Trans-Golgi network

Transport vesicle

9 Endocytosis^

Retrograde transport from later to earlier Golgi cisternae w

Plasma

9 Endocytosis^

membrane

Endocytic vesicle

Endocytic vesicle

Lysosome

Lysosome

Retrograde transport from later to earlier Golgi cisternae

Budding and fusion of ER-to-Golgi vesicles to form c/s-Golgi

Budding and fusion of ER-to-Golgi vesicles to form c/s-Golgi

Retrograde Golgi-to-ER transport

Rough ER

Protein synthesis on bound ribosomes; cotranslational transport of proteins into or across ER membrane

Retrograde Golgi-to-ER transport

M FIGURE 17-1 Overview of the secretory and endocytic pathways of protein sorting.

Secretory pathway: Synthesis of proteins bearing an ER signal sequence is completed on the rough ER (1), and the newly made polypeptide chains are inserted into the ER membrane or cross it into the lumen (Chapter 16). Some proteins (e.g., ER enzymes or structural proteins) remain within the ER. The remainder are packaged into transport vesicles ( 2) that bud from the ER and fuse together to form new c/s-Golgi cisternae. Missorted ER-resident proteins and vesicle membrane proteins that need to be reused are retrieved to the ER by vesicles ( 3) that bud from the c/s-Golgi and fuse with the ER. Each c/s-Golgi cisterna, with its protein content, physically moves from the c/s to the trans face of the Golgi complex ( 4) by a nonvesicular process called cisternal progression. Retrograde transport vesicles ( 5) move Golgi-resident proteins to the proper Golgi compartment. In all cells, certain soluble proteins move to the cell surface in transport vesicles ( 6) and are secreted continuously (constitutive secretion). In certain cell types, some soluble proteins are stored in secretory vesicles ( 7) and are released only after the cell receives an appropriate neural or hormonal signal (regulated secretion). Lysosome-destined membrane and soluble proteins, which are transported in vesicles that bud from the trans-Golgi ( 8), first move to the late endosome and then to the lysosome. Endocytic pathway: Membrane and soluble extracellular proteins taken up in vesicles that bud from the plasma membrane ( 9) also can move to the lysosome via the endosome.

Rough ER

Protein synthesis on bound ribosomes; cotranslational transport of proteins into or across ER membrane of at least three different kinds of vesicles. After budding from the trans-Golgi network, the first type of vesicle immediately moves to and fuses with the plasma membrane, releasing its contents by exocytosis. In all cell types, at least some proteins are loaded into such vesicles and secreted continuously in this manner. Examples of proteins released by such constitutive (or continuous) secretion include collagen by fibroblasts, serum proteins by hepatocytes, and antibodies by activated B lymphocytes. The second type of vesicle to bud from the trans-Golgi network, known as secretory vesicles, are stored inside the cell until a signal for exocyto-sis causes release of their contents at the plasma membrane. Among the proteins released by such regulated secretion are peptide hormones (e.g., insulin, glucagon, ACTH) from various endocrine cells, precursors of digestive enzymes from pancreatic acinar cells, milk proteins from the mammary gland, and neurotransmitters from neurons.

The third type of vesicle that buds from the trans-Golgi network is directed to the lysosome, an organelle responsible for the intracellular degradation of macromolecules, and to lysosome-like storage organelles in certain cells. Secretory proteins destined for lysosomes first are transported by vesicles from the trans-Golgi network to a compartment usually called the late endosome; proteins then are transferred to the lysosome by a mechanism that is not well understood but may involve direct fusion of the endosome with the lysoso-mal membrane. Soluble proteins delivered by this pathway include lysosomal digestive enzymes (e.g., proteases, glycosi-dases, and phosphatases) and membrane proteins (e.g., V-class proton pump) that pump H+ from the cytosol into the acidic lumen of the endosome and lysosome. As we will see, some of the specific protein-processing and -sorting events that take place within these organelles depend on their low luminal pH.

The endosome also functions in the endocytic pathway in which vesicles bud from the plasma membrane bringing membrane proteins and their bound ligands into the cell (see Figure 17-1). After being internalized by endocytosis, some proteins are transported to lysosomes, while others are recycled back to the cell surface. Endocytosis is a way for cells to take up nutrients that are in macromolecular form—for example, cholesterol in the form of lipoprotein particles and iron complexed with the serum protein transferrin. Endocy-tosis also can function as a regulatory mechanism to decrease signaling activity by withdrawing receptors for a particular signaling molecule from the cell surface.

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