Biology Reference
In-Depth Information
8.3 The Ubiquitin Proteasome System
The proteasome is the major site of degradation for misfolded or damaged pro-
teins, as well as for cell cycle regulators whose destruction drives cell cycle
transitions. Initially described as macropain, ingestin, or the multicatyltic pro-
teinase, the term proteasome was coined in 1988 (Arrigo et al.
1988
). The func-
tional proteasome within the cell is generally thought to be the 26S particle, and
consists of a catalytic 20S core particle and either of two regulatory particles
[reviewed in (Murata et al.
2009
; Navon and Ciechanover
2009
; Ravid and
Hochstrasser
2008
; Tomko
2011
). The 20S particle is a roughly 700 kDa hollow
cylinder formed by twenty eight subunits, two copies each of seven a and seven ß
subunits. The a and ß subunits are assembled into four rings, with the peptidase
activity coming from three of the ß subunits. The a subunits form the outer two
rings of the 20S particle and the ß subunits form the inner two rings, such that in
the assembled 20S particle access to the proteolytic core is limited by the narrow
opening afforded by the a subunits. Thus, insertion into the proteasome of proteins
destined for degradation is regulated by either the 19S or 11S regulatory particles
[reviewed in (Murata et al.
2009
; Tomko
2011
)].
The 11S particle regulates proteasome activity by making it more selective for
small peptides, and is thought to be involved in substrate processing during antigen
presentation. In contrast, the 19S particle contains many ATPase activities, dis-
plays chaperone activity in vitro, binds to proteins that have been covalently
modified with ubiquitin, and is thought to unfold proteins to allow their degra-
dation by the proteasome [reviewed in (Tomko
2011
)]. In general, proteins that are
degraded by the proteasome are targeted for degradation through ubiquitylation,
and thus the pathway leading up to proteasome degradation is often referred to as
the ubiquitin proteasome system (UPS) [reviewed in (Ravid and Hochstrasser
2008
)]. Ubiquitin is expressed as a precursor protein (either polyubiquitin, or a
fusion with an unrelated protein such as UBCEP80 that is a fusion of ribosomal
protein S27a and ubiquitin) that is proteolytically processed to generate free
ubiquitin. Free ubiquitin is then transferred to one or more lysine residues on target
proteins through an enzymatic cascade. In the only ATP-dependent step of
substrate ubiquitylation, free ubiquitin is coupled to the active site cysteine of an
E1, or ubiquitin-activating enzyme. Ubiquitin is then transferred from the E1 to the
active site cysteine of an E2, or ubiquitin-conjugating enzyme. In the final step an
E3 enzyme or ubiquitin ligase transfers ubiquitin to a lysine on the substrate
protein [reviewed in (Ravid and Hochstrasser
2008
; Rotin and Kumar
2009
;
Simpson-Lavy et al.
2010
).
There are many types of E3 ligases that fall into two major classes, the HECT-
(Homology to the E6-AP C-Terminus) and RING-type ligases [reviewed in (Rotin
and Kumar
2009
)]. In the case of the HECT-type ligases, ubiquitin is transferred to
an active site cysteine in a HECT domain containing protein as an intermediate in
the transfer of ubiquitin to substrate [reviewed in (Rotin and Kumar
2009
)]. In
contrast, RING-type ligases do not form this covalent intermediate with ubiquitin,
