Proteins move through cellular compartments to specific destinations

A scheme representing the possible flow of proteins along the ER ^ Golgi apparatus ^ plasma membrane route is shown in Figure 46-6. The horizontal arrows denote transport steps that may be independent of targeting signals, whereas the vertical open arrows represent steps that depend on specific signals. Thus, flow of certain proteins (including membrane proteins) from the ER to the plasma membrane (designated "bulk flow," as it is nonselective) probably occurs without any targeting sequences being involved, ie, by default. On the other hand, insertion of resident proteins into the ER and Golgi membranes is dependent upon specific signals (eg, KDEL or halt-transfer sequences for the ER). Similarly, transport of many enzymes to lysosomes is dependent upon the Man 6-P signal (Chapter 47), and a signal may be involved for entry of proteins into secretory granules. Table 46-4 summarizes information on sequences that are known to be involved in targeting various proteins to their correct intracellular sites.

CHAPERONES ARE PROTEINS THAT PREVENT FAULTY FOLDING & UNPRODUCTIVE INTERACTIONS OF OTHER PROTEINS

Exit from the ER may be the rate-limiting step in the secretory pathway. In this context, it has been found that certain proteins play a role in the assembly or proper folding of other proteins without themselves being components of the latter. Such proteins are called molecular chaperones; a number of important properties of these proteins are listed in Table 46-5, and the names of some of particular importance in the ER are listed in Table 46-6. Basically, they stabilize unfolded

Lysosomes o

Lysosomes

cis

medial

trans

ER

Golgi

Golgi

Golgi

o

o

o

o

Secretory storage vesicles

Cell surface

Secretory storage vesicles

Figure 46-6. Flow of membrane proteins from the endoplasmic reticulum (ER) to the cell surface. Horizontal arrows denote steps that have been proposed to be signal independent and thus represent bulk flow. The open vertical arrows in the boxes denote retention of proteins that are resident in the membranes of the organelle indicated. The open vertical arrows outside the boxes indicate signal-mediated transport to lysosomes and secretory storage granules. (Reproduced, with permission, from Pfeffer SR, Rothman JE: Biosynthetic protein transport and sorting by the endoplasmic reticulum and Golgi. Annu Rev Biochem 1987;56:829.)

Table 46-4. Some sequences or compounds that direct proteins to specific organelles.

Targeting Sequence or Compound

Organelle Targeted

Signal peptide sequence

Membrane of ER

Amino terminal KDELsequence (Lys-Asp-Glu-Leu)

Luminal surface of ER

Amino terminal sequence (20-80 residues)

Mitochondrial matrix

NLS1 (eg, Pro2-Lys2-Ala-Lys-Val)

Nucleus

PTS1 (eg, Ser-Lys-Leu)

Peroxisome

Mannose 6-phosphate

Lysosome

1NLS, nuclear localization signal; PTS, peroxisomal-matrix targeting sequence.

1NLS, nuclear localization signal; PTS, peroxisomal-matrix targeting sequence.

or partially folded intermediates, allowing them time to fold properly, and prevent inappropriate interactions, thus combating the formation of nonfunctional structures. Most chaperones exhibit ATPase activity and bind ADP and ATP. This activity is important for their effect on folding. The ADP-chaperone complex often has a high affinity for the unfolded protein, which, when bound, stimulates release of ADP with replacement by ATP. The ATP-chaperone complex, in turn, releases segments of the protein that have folded properly, and the cycle involving ADP and ATP binding is repeated until the folded protein is released.

Table 46-5. Some properties of chaperone proteins.

• Present in a wide range of species from bacteria to humans

• Many are so-called heat shock proteins (Hsp)

• Some are inducible by conditions that cause unfolding of newly synthesized proteins (eg, elevated temperature and various chemicals)

• They bind to predominantly hydrophobic regions of unfolded and aggregated proteins

• They act in part as a quality control or editing mechanism for detecting misfolded or otherwise defective proteins

• Most chaperones show associated ATPase activity, with ATP or ADP being involved in the protein-chaperone interaction

• Found in various cellular compartments such as cytosol, mitochondria, and the lumen of the endoplasmic reticulum

Table46-6. Some chaperones and enzymes involved in folding that are located in the rough endoplasmic reticulum.

• BiP (immunoglobulin heavy chain binding protein)

• GRP94 (glucose-regulated protein)

• Calreticulin

• PDI (protein disulfide isomerase)

• PPI (peptidyl prolyl cis-trans isomerase)

Several examples of chaperones were introduced above when the sorting of mitochondrial proteins was discussed. The immunoglobulin heavy chain binding protein (BiP) is located in the lumen of the ER. This protein will bind abnormally folded immunoglobulin heavy chains and certain other proteins and prevent them from leaving the ER, in which they are degraded. Another important chaperone is calnexin, a calcium-binding protein located in the ER membrane. This protein binds a wide variety of proteins, including mixed histocompatibility (MHC) antigens and a variety of serum proteins. As mentioned in Chapter 47, calnexin binds the monoglycosylated species of glycoproteins that occur during processing of glycoproteins, retaining them in the ER until the glycoprotein has folded properly. Calreticulin, which is also a calcium-binding protein, has properties similar to those of calnexin; it is not membrane-bound. Chaperones are not the only proteins in the ER lumen that are concerned with proper folding of proteins. Two enzymes are present that play an active role in folding. Protein disulfide isomerase (PDI) promotes rapid reshuffling of disulfide bonds until the correct set is achieved. Peptidyl prolyl isom-erase (PPI) accelerates folding of proline-containing proteins by catalyzing the cis-trans isomerization of X-Pro bonds, where X is any amino acid residue.

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