The Proteasome: Paradigm of a Self-Compartmentalizing Protease

Protein degradation is a necessity for many reasons: Homeostasis must be maintained while cellular structures are continually rebuilt, in particular during development or in response to external stimuli. Proteins misfolded as a consequence of mutations or ensuing from heat or oxidative stress must be scavenged because they are prone to aggregation. Beyond these more mundane "housekeeping" functions, protein degradation provides a means to terminate the lifespan of many regulatory proteins at distinct times; amongst them are cyclins, transcription factors, and components of signal transduction pathways Moreover, the immune system relies on the availability of immunocompetent peptides generated by the degradation of foreign antigens. However, since protein degradation is also a hazard, it must be subject to spatial and temporal control in order to prevent the destruction of proteins not destined for degradation. A basic stratagem in controlling protein degradation is compartmentalization, that is, the confinement of the proteolytic action to sites that can only be accessed by proteins displaying some sort of degradation signal. Such a compartment can be an organelle delimited by a membrane, as in the case of the lysosome. Proteins to be degraded must be imported into the lysosome via specific pathways, and the hydrolases carrying out the task must also be sorted from other proteins and are translocated by means of transport vesicles. Prokaryotic cells, possessing neither membrane-bound compartments nor vesicular transport systems, have developed a different form of compartmentalization, namely self- or autocompartmentalization. This principle is seen at work in several unrelated proteases that have all converged toward a common architecture in which proteolytic subunits self-assemble to form barrel-shaped complexes. These enclose inner cavities, which are several nanometers in diameter and harbor the active sites. Access to these inner compartments is usually restricted to unfolded polypeptides, which can pass through the narrow pores or channels guarding the entrance. The target proteins thus require interaction with a machinery capable of binding and presenting them in an unfolded form to the proteolytic core complexes; these interactions may be of either a transient or a continuous nature. Since protein folding and unfolding are closely related mechanistically, it is assumed, but not proven, that this task is performed by ATPase complexes, which bear some