One function of intracellular proteolytic mechanisms is to recognize and eliminate misfolded or otherwise abnormal proteins, as just described. Indeed, every protein in the cell eventually accumulates damage and is probably degraded by the proteasome. Yet another function of these proteolytic pathways is to confer short lifetimes on specific normal proteins whose concentrations must change promptly with alterations in the state of a cell. Some of these short-lived proteins are degraded rapidly at all times, while many others are conditionally short-lived; that is, they are metabolically stable under some conditions, but become unstable upon a change in the cell’s state. For example, mitotic cyclins are long-lived throughout the cell cycle until their sudden degradation at the end of mitosis, as explained in Chapter 17.
Figure 6–85 A hexameric protein unfoldase. (A) The proteasome cap includes proteins (orange) that recognize and hydrolyze ubiquitin and a hexameric ring (blue) through which ubiquitylated proteins are threaded. The hexameric ring is formed from six subunits, each belonging to the AAA family of proteins. (B) Model for the ATP-dependent unfoldase activity of AAA proteins. The ATP-bound form of a hexameric ring of AAA proteins binds a folded substrate protein that is held in place by its ubiquitin tag. A conformational change, driven by ATP hydrolysis, pulls the substrate into the central core and strains the ring structure. At this point, the substrate protein, which is being tugged upon, can partially unfold and enter further into the pore or it can maintain its structure and partially withdraw. Very stable protein substrates may require hundreds of cycles of ATP hydrolysis and dissociation before they are successfully pulled through the AAA protein ring. Once unfolded (and  de-ubiquitylated), the substrate protein moves relatively quickly through the pore  by successive rounds of ATP hydrolysis.  (A, adapted from G.C. Lander et al., Nature 482:186–191, 2012; B, adapted from
R.T. Sauer et al., Cell 119:9–18, 2004. With permission from Elsevier.)
N phosphorylation unmasking by creation of destabilizing by protein kinase protein dissociation N-terminus
How is such a regulated destruction of a protein controlled? Several general mechanisms are illustrated in Figure 6–86. Specific examples of each mechanism are discussed in later chapters. In one general class of mechanism (Figure 6–86A), the activity of a ubiquitin ligase is turned on either by E3 phosphorylation or by an allosteric transition in an E3 protein caused by its binding to a specific small or large molecule. For example, the anaphase-promoting complex (APC) is a multi-subunit ubiquitin ligase that is activated by a cell-cycle-timed subunit addition at mitosis. The activated APC then causes the degradation of mitotic cyclins and several other regulators of the metaphase–anaphase transition (see Figure 17–15A).
Alternatively, in response either to intracellular signals or to signals from the environment, a degradation signal can be created in a protein, causing its rapid ubiquitylation and destruction by the proteasome (Figure 6–86B). One common way to create such a signal is to phosphorylate a specific site on a protein that unmasks a normally hidden degradation signal. Another way to unmask such a signal is by the regulated dissociation of a protein subunit. Finally, powerful degradation signals can be created by cleaving a single peptide bond, provided that this cleavage creates a new N-terminus that is recognized by a specific E3 protein as a “destabilizing” N-terminal residue. This E3 protein recognizes only certain amino acids at the N-terminus of a protein; thus not all protein-cleavage events will lead to degradation of the C-terminal fragment produced.
In humans, nearly 80% of proteins are acetylated on their N-terminal residue, and we now know that this modification is recognized by a specific E3 enzyme,