Protein Targeting

Abstract

Protein sorting is the process by which cellular proteins, both newly synthesised and recycling, are directed to the appropriate intracellular compartments in which they will perform their function. This process relies upon the targeting signals that are found within each protein. These specific signals can be integrally encoded within the polypeptide sequence or require post‐translational modification of the protein. Targeting signals direct the interaction of proteins with a multitude of accessory factors to ensure the correct delivery of proteins to their appropriate destinations within each cell. Many proteins have multiple targeting signals that are interpreted hierarchically in cellular compartments. Changes in the expression of either the targeting signals or their recognition factors alter the targeting of proteins in different cell types or in response to physiological cues.

Key Concepts:

  • Protein targeting signals can be encoded within the polypeptide chain or can be post‐translational modifications or patches.

  • Targeting signals are recognised by cellular factors that direct proteins to their proper site of function.

  • Many proteins have multiple targeting signals.

  • The relative strength of targeting signals can change based on post‐translational modifications such as phosphorylation or accessibility to recognition factors at different locations within cells.

  • Differences in the expression of targeting signals or recognition factors can result in cell‐type dependent, developmental, or acute changes in protein targeting.

Keywords: cytoskeleton; transport vesicles; membrane fusion; membrane domains; apical; basolateral

Figure 1.

Biosynthetic and endocytic pathways in cells. Transmembrane proteins (red lollipops) destined for cell surface delivery are synthesised in the ER (which is contiguous with the outer membrane of the nuclear envelope), transit the Golgi complex, and are packaged into vesicles leaving the trans‐Golgi network (TGN). These vesicles fuse directly with the plasma membrane (1) or first deposit their cargo in endosomal compartments (2). Vesicles interact with microtubules and actin filaments as they move to the cell surface. Exocytosis of the vesicles and insertion of the cargo into the plasma membrane are controlled by ‘SNAREs’ and accessory proteins (see text). Proteins reside at the cell surface (3) or are retrieved into endocytic vesicles by clathrin‐mediated or other pathways (4). Internalised cargo can be recycled to the cell surface (5) or targeted deeper into the endocytic pathway for degradation in lysosomes (lys; 6).

Figure 2.

Maintaining distinct apical, basolateral, and ciliary domains with different protein and lipid compositions is essential for epithelial cell function. (a) The schematic shows the segregations of apical (green), basolateral (orange), and ciliary (blue) proteins in distinct domains in a typical polarised epithelial cell. Apical and basolateral domains are physically separated by tight junctions (TJs); how ciliary proteins are delivered and prevented from diffusing into the apical membrane and vice versa is not well understood. (b) In this section of a kidney collecting duct, double‐staining by indirect immunofluorescence reveals the distinct apical versus basolateral membrane polarity of two important membrane proteins in proton‐secreting intercalated cells. The vacuolar proton pumping ATPase (green) is confined to the apical membrane (and some subapical intracellular vesicles), whereas the chloride–bicarbonate exchanger AE1 (orange) is restricted to the basolateral plasma membrane of these cells. TJs that separate the apical and basolateral cell domains are marked by small arrows. Adjacent principal cells in the same epithelium are not stained with either of these antibodies, and appear as dark gaps or holes in the epithelial lining (asterisks).

Figure 3.

Some proteins show a remarkable intracellular redistribution after activation of various signal transduction pathways. In this case, the AQP2 water channel, transfected into porcine kidney epithelial LLC‐PK1 cells, is located on perinuclear vesicles under nonstimulated, baseline conditions (arrows in (a)). After 10 min exposure to vasopressin, which results in an increase in intracellular cyclic adenosine monophosphate (cAMP), translocation of vesicles containing AQP2 is activated and the protein is inserted by exocytosis into the plasma membrane (arrows in (b)).

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Further Reading

Lin S, Naim HY and Roth MG (1997) Tyrosine‐dependent basolateral sorting signals are distinct from tyrosine‐dependent internalization signals. Journal of Biological Chemistry 272: 26300–26305.

Paladino S, Sarnataro D, Pillich R et al. (2004) Protein oligomerization modulates raft partitioning and apical sorting of GPI‐anchored proteins. Journal of Cell Biology 167: 699–709.

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Zimmermann R, Eyrisch S, Ahmad M and Helms V (2011) Protein translocation across the ER membrane. Biochimica et Biophysica Acta 1808: 912–924.

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How to Cite close
Weisz, Ora A(Jun 2014) Protein Targeting. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005291.pub2]