Substrate selection by the proteasome through initiation regions

Abstract

Proteins in the cell have to be eliminated once their function is no longer desired or they become damaged. Most regulated protein degradation is achieved by a large enzymatic complex called the proteasome. Many proteasome substrates are targeted for degradation by the covalent attachment of ubiquitin molecules. Ubiquitinated proteins can be bound by the proteasome, but for proteolysis to occur the proteasome needs to find a disordered tail somewhere in the target at which it initiates degradation. The initiation step contributes to the specificity of proteasomal degradation. Here, we review how the proteasome selects initiation sites within its substrates and discuss how the initiation step affects physiological processes.

Keywords: initiation region; proteasome; protein degradation; protein unfolding; ubiquitin.

Figure 1

Structure of the 26S proteasome (based on PDB: 4CR2). The 26S proteasome consists of a 20S CP (orange) and a 19S RP (gray or indicated colors). The CP is responsible for proteolysis. The RP contains the ATPase subunits Rpt1–6 (purple), the deubiquitinase Rpn11 (cyan), and the ubiquitin receptors Rpn1, Rpn10, and Rpn13 (green). Substrates enter the proteasome through a channel at the center of a ring formed by the ATPase subunits.

Figure 2

The proteasomal degradation signal has two parts. (a) Schematic representation of a proteasome substrate. A substrate protein (green) has to contain a proteasome‐binding tag (typically poly‐ubiquitin chains, yellow) and an unstructured region (red) for efficient degradation. (b) Substrate engagement by the proteasome. The proteasome recognizes a substrate via the ubiquitin tag and engages it at the disordered region for unfolding and translocation from the 19S RP to 20S CP.

Figure 3

Initiation site selection by the proteasome. (a–c) Requirements for effective initiation regions. The initiation region has to be long enough (a), with a suitable amino acid composition (b), and be located in a position accessible to the proteasome (c). (d) Initiation of proteasomal degradation in trans. The proteasome can recognize a protein complex through ubiquitinated subunits (yellow and blue) but degrades only subunits with accessible initiation regions (green and red). (e) Speculative models of substrate recognition via degradation adaptors. The proteasome may recognize substrates through adaptor proteins (pink and orange) that recognize the ubiquitin chain attached to a substrate or the substrate directly without ubiquitination.