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Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.

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Molecular Cell Biology. 4th edition.

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Chapter 17Protein Sorting: Organelle Biogenesis and Protein Secretion

Firefly luciferase, a peroxisomal matrix protein, is transported to peroxisomes of normal human fibroblasts, but remains cytoplasmic in cells from a Zellweger syndrome patient

Firefly luciferase, a peroxisomal matrix protein, is transported to peroxisomes of normal human fibroblasts, but remains cytoplasmic in cells from a Zellweger syndrome patient. The fibroblasts (on coverslips) were microinjected with mRNA encoding the luciferase. After overnight incubation in a humidified CO2 incubator, the cells were fixed, permeabilized, and labeled with appropriate primary (rabbit anti-luciferase) and secondary (FITC anti-rabbit) antibodies. The punctate immunofluorescence observed in normal human HS68 cells (left) is indicative of peroxisomal luciferase. The fibrobrast cell line (GM6231) from the human patient (right) does not import luciferase into peroxisomes, but shows a cytoplasmic signal instead of the punctate signal. Magnification 165X. [See P. Walton et al., 1993, Mol. Cell Biol. 12:531 – 541; photographs courtesy of Suresh Subramani.]

A typical mammalian cell contains up to 10,000 different kinds of proteins; a yeast cell, about 5000. For a cell to function properly, each of its numerous proteins must be localized to the correct cellular membrane or aqueous compartment (e.g., the mitochondrial matrix, chloroplast stroma, lysosomal lumen, or cytosol). Hormone receptor proteins, for example, must be delivered to the plasma membrane if the cell is to recognize hormones, and specific ion-channel and transporter proteins are needed if the cell is to import or export the corresponding ions and small molecules. Water-soluble enzymes such as RNA and DNA polymerases must be targeted to the nucleus; still others, such as proteolytic enzymes or catalase, must go to lysosomes or peroxisomes, respectively. Many proteins, such as hormones and components of the extracellular matrix, must be directed to the cell surface and secreted.

The process of directing each newly made polypeptide to a particular destination — referred to as protein targeting, or protein sorting — is critical to the organization and functioning of eukaryotic cells. This process occurs at several levels. As discussed in Section 9.7, a few proteins, encoded by the DNA present in mitochondria and chloroplasts, are synthesized on ribosomes in these organelles and are incorporated directly into compartments within these organelles. However, most mitochondrial and chloroplast proteins and all of the proteins in the other organelles, particles, and membranes of a eukaryotic cell are encoded by nuclear DNA, are synthesized on ribosomes in the cytosol, and are distributed to their correct destinations via the sequential action of several sorting signals and multiple sorting events. How nuclear-encoded organelle, membrane, and secretory proteins are sorted to their correct destinations are the major subjects of this chapter.

The first sorting event occurs during initial growth of nascent polypeptide chains on cytosolic ribosomes (Figure 17-1). Some nascent proteins contain, generally at the amino terminus, a specific signal, or targeting, sequence that directs the ribosomes synthesizing them to the endoplasmic reticulum (ER). Protein synthesis is completed on ribosomes attached to the rough ER membrane (the presence of these bound ribosomes distinguishes the rough ER from the smooth ER). The completed polypeptide chains then move to the Golgi complex and subsequently are sorted to various destinations. Proteins synthesized and sorted in this pathway, referred to as the secretory pathway, include not only those that are secreted from the cell but also enzymes and other resident proteins in the lumen of the ER, Golgi, and lysosomes as well as integral proteins in the membranes of these organelles and the plasma membrane.

Figure 17-1. Overview of sorting of nuclear-encoded proteins in eukaryotic cells.

Figure 17-1

Overview of sorting of nuclear-encoded proteins in eukaryotic cells. All nuclear-encoded mRNAs are translated on cytosolic ribosomes. Ribosomes synthesizing nascent proteins in the secretory pathway 1  are directed to the rough endoplasmic (more...)

Synthesis of all other nuclear-encoded proteins is completed on “free” cytosolic ribosomes, and the completed proteins are released into the cytosol. These proteins remain in the cytosol unless they contain a specific signal sequence that directs them to the mitochondrion, chloroplast, peroxisome, or nucleus (see Figure 17-1). Many of these proteins are subsequently sorted further to reach their correct destinations within these organelles; such sorting events depend on yet other signal sequences within the protein. Each sorting event involves binding of a signal sequence to one or more receptor proteins on the surface or interior of the organelle.

In this chapter, we detail the mechanisms whereby proteins are sorted to the major organelles and compartments of the cell. (The transport of proteins in and out of the nucleus through nuclear pores, which occurs by somewhat different mechanisms, is discussed in Section 11.4.) The first two sections cover targeting of proteins to mitochondria, chloroplasts, and peroxisomes. The next several sections describe the various components and events in the secretory pathway, including the post-translational modifications that occur to proteins as they move through this pathway. We then discuss how proteins are internalized into cells following binding to specific cell-surface receptors and the fate of such internalized proteins. In the final section, we describe how the various small membrane-bounded vesicles that carry proteins within cells are formed and deliver their contents to specific destinations.

Key Terms

  • A, B, O antigens
  • assembly particles
  • chaperones
  • cisternal progression
  • clathrin-coated vesicles
  • constitutive secretion
  • COP I vesicles
  • COP II vesicles
  • cotranslational transport
  • endocytic pathway
  • GPI anchor
  • late endosome
  • mannose 6-phosphate (M6P) sorting pathway
  • membrane-anchor sequence
  • N- and O-linked oligosaccharides
  • regulated secretion
  • secretory pathway
  • signal-recognition particle (SRP)
  • stop-transfer sequences
  • topogenic sequences
  • transcytosis
  • T-SNAREs
  • V-SNAREs


  • 17.1. Synthesis and Targeting of Mitochondrial and Chloroplast Proteins
  • 17.2. Synthesis and Targeting of Peroxisomal Proteins
  • 17.3. Overview of the Secretory Pathway
  • 17.4. Translocation of Secretory Proteins across the ER Membrane
  • 17.5. Insertion of Membrane Proteins into the ER Membrane
  • 17.6. Post-Translational Modifications and Quality Control in the Rough ER
  • 17.7. Protein Glycosylation in the ER and Golgi Complex
  • 17.8. Golgi and Post-Golgi Protein Sorting and Proteolytic Processing
  • 17.9. Receptor-Mediated Endocytosis and the Sorting of Internalized Proteins
  • 17.10. Molecular Mechanisms of Vesicular Traffic
  • PERSPECTIVES for the Future
  • PERSPECTIVES in the Literature
  • Testing Yourself on the Concepts
  • MCAT/GRE-Style Questions
  • References

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
Bookshelf ID: NBK21480


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