The recognition of ubiquitinated proteins by the proteasome

Abstract

The ability of ubiquitin to form up to eight different polyubiquitin chain linkages generates complexity within the ubiquitin proteasome system, and accounts for the diverse roles of ubiquitination within the cell. Understanding how each type of ubiquitin linkage is correctly interpreted by ubiquitin binding proteins provides important insights into the link between chain recognition and cellular fate. A major function of ubiquitination is to signal degradation of intracellular proteins by the 26S proteasome. Lysine-48 (K48) linked polyubiquitin chains are well established as the canonical signal for proteasomal degradation, but recent studies show a role for other ubiquitin linked chains in facilitating degradation by the 26S proteasome. Here, we review how different types of polyubiquitin linkage bind to ubiquitin receptors on the 26S proteasome, how they signal degradation and discuss the implications of ubiquitin chain linkage in regulating protein breakdown by the proteasome.

Keywords: Polyubiquitin chains; Proteasome; Ubiquitin; Ubiquitin binding domain; Ubiquitin binding protein; Ubiquitin receptors.

Fig. 1

Proteasome ubiquitin receptors. Schematic of the 26S proteasome illustrating the position of the intrinsic proteasome receptors (a) and the association of the UBA–Ubl proteins with the 19S proteasome (b). Rpn10 and Rpn13 are the predominant high affinity sites for binding ubiquitinated proteins. In yeast, Rpn1 may also facilitate binding of ubiquitinated proteins to the 19S (a). Ubl–UBA proteins, such as Rad23 and Dsk2, associate with the 26S through their Ubl domains that bind to either Rpn10 or Rpn13. The UBA domains bind the polyubiquitin chains (b)

Fig. 2

Recognition of different ubiquitin linkages by the 26S proteasome. Schematic of the interaction of the 26S proteasome with different types of ubiquitin linkages. The positions of Rpn13 and Rpn10 within the proteasome are highlighted (dark blue). K48-polyubiquitinated proteins are the canonical signal for proteasome-mediated degradation (a). K63-polyubiquitin chains are blocked from binding to the 26S due to K63-selective ubiquitin binding proteins, which bind tightly to the K63-polyubiquitin chains and direct them to alternative pathways (endosomal–lysosomal pathway) (b). Homotypic K11-polyubiquitin chains do not bind tightly to the 19S proteasome receptors (c). Heterotypic K11/K48-polyubiquitinated proteins signal proteasome-mediated degradation of cell-cycle substrates (e.g., cyclin B1) (d). Multiple monoubiquitination can facilitate the degradation of some proteasome substrates (cyclin B1) (e). Short proteins (less than 150 amino acids) may be targeted for degradation by a single ubiquitin moiety (f). Ub ubiquitin