Figure 6–82 The processes that monitor protein quality following protein synthesis. A newly synthesized protein sometimes folds correctly and assembles on its own with its partner proteins, in which case the quality control mechanisms leave it alone. Incompletely folded proteins are helped to properly fold by molecular chaperones: first by a family of hsp70 proteins, and then, in some cases, by hsp60-like proteins. For both types of chaperones, the substrate proteins are recognized by an abnormally exposed patch of hydrophobic amino acids on their surface. These “protein-rescue” processes compete with another mechanism that, upon recognizing an abnormally exposed hydrophobic patch, marks the protein for destruction by the proteasome. The combined activity of all of these processes is needed to prevent massive protein aggregation in a cell, which can occur when many hydrophobic regions on proteins clump together nonspecifically.
Figure 6–83 The proteasome. (A) A cutaway view of the structure of the central 20S cylinder, as determined by x-ray crystallography, with the active sites of the proteases indicated by red dots. (B) The entire proteasome, in which the central cylinder (yellow) is supplemented by a 19S cap (blue) at each end. The complex cap (also called the regulatory particle) selectively binds proteins that have been marked by ubiquitin for destruction; it then uses ATP hydrolysis to unfold their polypeptide chains and feed them through a narrow channel (see Figure 6–85) into the inner chamber of the 20S cylinder for digestion to short peptides. (B, from
W. Baumeister et al., Cell 92:367–380, 1998. With permission from Elsevier.)
Present in many copies dispersed throughout the cytosol and the nucleus, the proteasome also destroys aberrant proteins that have entered the endoplasmic reticulum (ER). In the latter case, an ER-based surveillance system detects proteins that have failed either to fold or to be assembled properly after they enter the ER, and retrotranslocates them back to the cytosol for degradation by the proteasome (discussed in Chapter 12).
Each proteasome consists of a central hollow cylinder (the 20S core proteasome) formed from multiple protein subunits that assemble as a stack of four heptameric rings (Figure 6–83). Some of the subunits are proteases whose active sites face the cylinder’s inner chamber, thus preventing them from running rampant through the cell. Each end of the cylinder is normally associated with a large protein complex (the 19S cap) that contains a six-subunit protein ring through which target proteins are threaded into the proteasome core, where they are degraded (Figure 6–84). The threading reaction, driven by ATP hydrolysis, unfolds the target proteins as they move through the cap, exposing them to the proteases lining the proteasome core (Figure 6–85). The proteins that make up the ring structure in the proteasome cap belong to a large class of protein “unfoldases” known as AAA proteins. Many of them function as hexamers, and they share mechanistic features with the ATP-dependent DNA helicases that unwind DNA (see Figure 5–14).
(A) (B) ubiquitin target protein with receptor polyubiquitin chain