Sorting, proteins

The biosynthesis of all proteins starts on free ribosomes (top). However, the paths that the proteins follow soon diverge, depending on which target they are destined for. Proteins that carry a signal peptide for the i (1) follow the secretory pathway (right). Proteins that do not have this signal follow the cytoplasmic pathway (left). 

Secretory pathway. Ribosomes that synthesize a protein with a signal peptide for the ER settle on the ER (see p. 228). The peptide chain is transferred into the lumen of the rER. The presence or absence of other signal sequences and signal regions determines the subsequent transport pathway. 

Cytoplasmic pathway. Proteins that do not have a signal peptide for the ER are synthesized in the cytoplasm on free ribosomes, and remain in that compartment. Special signals mediate further transport into the mitochondria (5 see p. 232), the nucleus (6 see p. 208) or peroxisomes (7). 

After they have been used, signal peptides at the N terminus are cleaved off by specific hydrolases (symbol scissors). In proteins that contain several successive signal sequences, this process can expose the subsequent signals. By contrast, signal peptides that have to be read several times are not cleaved. 

Exocytosis is a term referring to processes that allow cells to expel substances (e.g., hormones or neurotransmitters) quickly and in large quantities. Using a complex protein machinery, secretory vesicles fuse completely or partially with the plasma membrane and release their contents. Exocytosis is usually regulated by chemical or electrical signals. As an example, the mechanism by which neurotransmitters are released from synapses (see p. 348) is shown here, although only the most important proteins are indicated. 

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Rothman JE, Wieland FT (1996) Protein sorting by transport vesicles. Science 272 227-234... 

Protein Folding Problem Protein Kinase Protein Kinase A Protein Kinase C Protein Kinase Inhibitors Protein Phosphatases Protein Sorting... 

Mays, R.W., Beck, K.A.. Nelson, W.J. (1994). Organization and function of the cytoskeleton in polarized epithelial cells a component of the protein sorting machinery. Curr. Opin. Cell Biol. 6, 16-24. 

Haiti, F.-U. Neupert, W. (1990). Protein sorting to mitochondria Evolutionary conservations of folding and assembly. Science 247, 930-937. 

Figure 46-1. Diagrammatic representation of the two branches of protein sorting occurring by synthesis on (1) cytosolic and (2) membrane-bound polyribosomes. The mitochondrial proteins listed are encoded by nuclear genes. Some of the signals used in further sorting of these proteins are listed in Table 46-4. (ER, endoplasmic reticulum GA, Golgi apparatus.)...

Lodish H et al Molecular Cell Biology, 4th ed. Freeman, 2000. (Chapter 17 contains comprehensive coverage of protein sorting and organelle biogenesis.)... 

Cacia, J., Quan, C. P., Vasser, M., Sliwkowski, M. B., and Frenz, J., Protein sorting by high-performance liquid chromatography I. Biomimetic interaction chromatography of recombinant human deoxyribonuclease I on polyionic stationary phases, /. Chromatogr., 634, 229, 1993. 

Lundbaek, J. A., Andersen, O. S., Werge, T. and Nielsen, C. Cholesterol-induced protein sorting an analysis of energetic feasibility. Biophys. J. 84 2080-2089, 2003. 

Beck, K. A. and Nelson, I. The spectrin-based membrane skeleton as a membrane protein-sorting machine. Am.. Physiol. 270 C1263-C1270,1996. 

The biosynthetic, secretory pathway is responsible for protein sorting and delivery and allows, among other functions, for cell-cell communication through secreted products. This delivery process starts at the endoplasmic reticulum (ER), to finish in the cell plasma membrane or, in some cases, in specific intracellular organelles. To accomplish this, specific proteins must be properly directed to the correct destination, while other proteins are retained as residents within specific organelles along the way. 

Schmid, S. L. Clathrin-coated vesicle formation and protein sorting an integrated process. Annu. Rev. Biochem. 66 511-548,1997. 

Saraste, J. and Kuismanen, E. Pathways of protein sorting and membrane traffic between the rough endoplasmic reticulum and the Golgi complex. Semin. Cell Biol. 3 343-355,1992. 

PROTEIN SORTING SIGNALS AND PREDICTION OF SUBCELLULAR LOCALIZATION... 

As described in Section II,A, gram-positive bacteria have only one membrane (the cytoplasmic membrane). Therefore, the translocation through the Sec pathway directly leads proteins to be secreted (Simonen and Palva, 1993 Nagarajan, 1993). The issue of protein sorting into the cell wall is described in a separate section. 

In spite of the variety of appearances of eukaryotic cells, their intracellular structures are essentially the same. Because of their extensive internal membrane structure, however, the problem of precise protein sorting for eukaryotic cells becomes much more difficult than that for bacteria. Figure 4 schematically illustrates this situation. There are various membrane-bound compartments within the cell. Such compartments are called organelles. Besides the plasma membrane, a typical animal cell has the nucleus, the mitochondrion (which has two membranes see Fig. 6), the peroxisome, the ER, the Golgi apparatus, the lysosome, and the endosome, among others. As for the Golgi apparatus, there are more precise distinctions between the cis, medial, and trans cisternae, and the TGN trans Golgi network) (see Fig. 8). In typical plant cells, the chloroplast (which has three membranes see Fig. 7) and the cell wall are added, and the lysosome is replaced with the vacuole. 

The GPI-anchored proteins are related to various cellular functions. For example, they participate in the protein sorting to the apical surface of polarized cells and clathrin-independent endocytosis (see Section III,... 

The mechanisms of ER protein sorting are relatively well known (Teas-dale and Jackson, 1996). Most, if not all, soluble ER proteins have a well-conserved C-terminal tetrapeptide, KDEL ( HDEL for yeasts) in addition to a cleavable N-terminal signal peptide. A small set of membrane proteins also has this signal at the C terminus. This signal... 

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