The protein biosynthetic pathways in cells can be considered to be one large sorting system. Many proteins carry signals (usually but not always specific sequences of amino acids known as targeting sequences) that direct them to their specific subcellular destinations; these signals are a fundamental component of the sorting system. Usually, the signal sequences are recognized by and interact with complementary areas of other proteins that serve as receptors.

A major sorting decision is made early in protein bio synthesis, when specific proteins are synthesized either on cytosolic (free) or membrane-bound polyribosomes. The signal hypothesis was proposed by Blobel and Sabatini in 1971 partly to explain the distinction between free and membrane-bound polyribosomes. They proposed that proteins synthesized on membrane-bound polyribosomes contain an N-terminal signal peptide, which causes them to become attached to the membranes of the endoplasmic reticulum (ER), and facilitates protein transfer into the ER lumen. On the other hand, proteins synthesized on free polyribosomes lack the signal peptide and retain free movement in the cytosol. An important aspect of the signal hypothesis is that all ribosomes have the same structure, and that the distinction between membrane-bound and free ribosomes depends solely on the former carrying proteins that have signal peptides. Because many membrane proteins are synthesized on membrane-bound polyribosomes, the signal hypothesis plays an important role in concepts of membrane assembly. ER regions containing attached polyribosomes are called the rough ER (RER), and the distinction between the two types of ribosomes results in two branches of the protein-sorting pathway, called the cytosolic branchand the RER branch (Figure 1).

Fig1. The two branches of protein sorting. Proteins are synthesized on cytosolic (free) polyribosomes or membrane-bound polyribosomes in the rough endoplasmic reticulum. Mitochondrial proteins encoded by nuclear genes are derived from the cytosolic pathway. (ER; endoplasmic reticulum; GA, Golgi apparatus; RER, rough endoplasmic reticulum.)

Proteins synthesized by cytosolic polyribosomes are directed to mitochondria, nuclei, and peroxisomes by specific signals, or remain in the cytosol if they lack a signal. Any protein that contains a targeting sequence that is subsequently removed is designated as a preprotein. In some cases, a second peptide is also removed, and in that event the original, newly synthesized protein is known as a preproprotein (eg, preproalbumin).

Proteins synthesized and sorted in the RER branch (see Figure 1) include many destined for various membranes (eg, of the ER, Golgi apparatus [GA], plasma membrane [PM]), and also lysosomal enzymes. In addition, proteins for export from the cell via exocytosis (secretion) are synthesized via this route. These various proteins may thus reside in the membranes or lumen of the ER, or follow the major transport route of intracellular proteins to the GA. In the secretory or exocytotic pathway, proteins are transported from the ER → GA → PM and then released into the external environment. Secretion may be constitutive, meaning that transport occurs continuously, or regulated, where transport is switched on and off as required. Proteins destined for the GA, the PM, certain other sites, or for constitutive secretion are carried in transport vesicles (Figure 2). Other proteins which are subject to regulated secretion are carried in secretory vesicles (see Figure 2). These are particularly prominent in the pancreas and certain other glands.

Fig2. The rough ER branch of protein sorting. Newly synthesized proteins are inserted into the ER membrane or lumen from membrane-bound polyribosomes (small black circles studding the cytosolic face of the ER). Proteins that are transported out of the ER are carried in COPII vesicles to the cis-Golgi (anterograde transport). Proteins move through the Golgi as the cisternae (membrane sac-like structures) mature. In the trans-Golgi network (TGN), the exit side of the Golgi, proteins are segregated and sorted. For regulated secretion, proteins accumulate in secretory vesicles, while proteins destined for insertion in the plasma membrane for constitutive secretion are carried to the cell surface in trans port vesicles. Clathrin-coated vesicles are involved in endocytosis, carrying cargo to late endosomes and to lysosomes. Mannose 6-phosphate (not shown; see Chapter 46) acts as a signal for transporting enzymes to lysosomes. COPI vesicles transport protein from GA to the ER (retrograde transport) and may be involved in some intra-Golgi transport. Cargo normally passes through the ER-Golgi intermediate complex (ERGIC) compartment to the GA. (Reproduced with permission from E Degen.)

The Golgi Apparatus Is Involved in Glycosylation & Sorting of Proteins

 The GA plays two major roles in protein synthesis. First, it is involved in the processing of the oligosaccharide chains of membrane and other N-linked glycoproteins and also contains enzymes involved in O-glycosylation. Second, it is involved in the sorting of various proteins prior to their delivery to their appropriate intracellular destinations. The GA consists of cis- (facing the ER), medial and trans cisternae (membrane stacks), and the trans-Golgi network (TGN) (see Figure 2). All parts of the GA participate in oligosaccharide chain processing, whereas the TGN is particularly involved in protein sorting, and is very rich in vesicles.

Chaperones Are Proteins That Stabilize Unfolded or Partially Folded Proteins

Molecular chaperones are proteins which stabilize unfolded or partially folded intermediates, allowing them time to fold covalently and preventing inappropriate interactions, thus com bating the formation of nonfunctional structures. Three families of these proteins are known, Hsp70, Hsp 90, and Hsp33. Most chaperones exhibit ATPase activity and bind ADP and ATP. This activity is important for their effect on protein folding.

The ADP-chaperone complex often has a high affinity for the unfolded protein, which, when bound, stimulates the replacement of ADP with 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 protein is released. Chaperones are required for the correct targeting of proteins to their subcellular locations. A number of important properties of these proteins are listed in Table 1.

Table1. Some Properties of Chaperone Proteins

Chaperoninsare a second type of chaperone which enable the correct folding of denatured proteins. They also differ from chaperones in that they are much larger, being oligomers with a molecular weight of 800 kDa as compared to monomers of 70 to 100 kDa. The structure of the bacterial chaperonin GroEL/GroES has been studied in detail. It has two ring-like structures, each composed of seven identical subunits, which form barrel-like shape, and again ATP is involved in its action. Its structure allows it to sequester an unfolded protein away from other proteins, giving it time and suitable conditions to fold properly. The heat shock protein Hsp60 is the equivalent of GroEL in eukaryotes.

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