The proteasome: overview of structure and functions

Abstract

The proteasome is a highly sophisticated protease complex designed to carry out selective, efficient and processive hydrolysis of client proteins. It is known to collaborate with ubiquitin, which polymerizes to form a marker for regulated proteolysis in eukaryotic cells. The highly organized proteasome plays a prominent role in the control of a diverse array of basic cellular activities by rapidly and unidirectionally catalyzing biological reactions. Studies of the proteasome during the past quarter of a century have provided profound insights into its structure and functions, which has appreciably contributed to our understanding of cellular life. Many questions, however, remain to be elucidated.

Fig. 1

Schematic diagram of the 26S proteasome. Left panel: Averaged image of the rat 26S proteasome complex based on electron micrographs. Photograph kindly provided by W. Baumeister. U, ubiquitin. Middle panel: The overall tertiary structure of the bovine 20S proteasome (central portion); the structures of the 19S RPs have not yet been determined (the pair of symmetrically disposed terminal structures depicted by question marks). Right panel: Schematic drawing of the subunit structure. CP, core particle (20S proteasome); RP, 19S regulatory particle consisting of the base and lid subcomplexes; Rpn, RP non-ATPase; Rpt, RP triple-ATPase.

Fig. 2

Schematic diagram of proteolysis by the 26S proteasome. Positions of subunits indicated (i.e., Rpn10, Rpn13, Rpn11, Rpt1-Rpt6, β1, β2 and β5 are represented in Fig. 1. The β1, β2 and β5 subunits are associated with caspase-like, trypsin-like and chymotrypsin-like activities, respectively (for details, see text).

Fig. 3

Schematic representation of diverged proteasomes. 20S proteasomes are responsible for the proteolytic activity of the proteasomes and are composed of 28 subunits arranged as a cylinder containing four heteroheptameric rings with an α_1–7β_1–7β_1–7α_1–7 arrangement (middle-upper drawing, constitutive or standard proteasomes). In vertebrates, the β1i, β2i and β5i subunits are expressed in response to IFN-γ and are preferentially incorporated into proteasomes, resulting in the immunoproteasomes (left). The newly identified β5t catalytic subunit of 20S proteasomes is incorporated in place of β5 or β5i, together with β1i and β2i to form thymoproteasomes, which are specifically found in cTECs (right). The middle-lower drawing represents the putative testis-specific proteasome, in which α4 of mammalian standard proteasomes is replaced by a novel subunit, α8.

Fig. 4

A schematic model of mammalian 20S proteasome assembly. The PAC1–PAC2 and PAC3–PAC4 heterodimeric complexes are involved in the formation of the α-ring. Then, sequential incorporation of the β subunits begins with the binding of β2 and hUmp1 on the α-ring. hUmp1 is required for the association of β2 in early assembly intermediates. PAC3–PAC4, which is released at the time of β3 association, maintains the structural integrity of the intermediates until β3 is incorporated on the α-ring. The subsequent ordered incorporation of other β subunits is assisted by intramolecular chaperones, such as the propeptides of β2 and β5 and the C-terminal tail of β2. Dimerization of half-mers (i.e., half-proteasomes lacking β7) is assisted by the C-terminal tail of β7. This is followed by removal of the β subunit propeptides (β1, β2, β5, β6 and β7) as well as hUmp1 and PAC1–PAC2 degradation. Note that the role of Ump1 for dimerization of half-proteasomes or checkpoint of half-mers is emphasized in yeast, but its exact role is somewhat difference in mammals (for details, see text).