Paradigms of protein degradation by the proteasome - PubMed (original) (raw)

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Paradigms of protein degradation by the proteasome

Tomonao Inobe et al. Curr Opin Struct Biol. 2014 Feb.

Abstract

The proteasome is the main proteolytic machine in the cytosol and nucleus of eukaryotic cells where it degrades hundreds of regulatory proteins, removes damaged proteins, and produces peptides that are presented by MHC complexes. New structures of the proteasome particle show how its subunits are arranged and provide insights into how the proteasome is regulated. Proteins are targeted to the proteasome by tags composed of several ubiquitin moieties. The structure of the tags tunes the order in which proteins are degraded. The proteasome itself edits the ubiquitin tags and drugs that interfere in this process can enhance the clearance of toxic proteins from cells. Finally, the proteasome initiates degradation at unstructured regions within its substrates and this step contributes to substrate selection.

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Figures

Figure 1

Figure 1

Structure of the 26S proteasome. Molecular surface of the 19S activator particle bound to the 20S core particle (PDB 4C0V) (left). The 20S core particle is composed of central two β rings (dark red) and outer two α rings (light red) at either end. The 19S regulatory particle, which contains AAA ATPase subunits (blue) and non-ATPase subunits (yellow), caps either end of the 20S. Cross section reveals the degradation channel that connects the proteolytic chamber in the 20S core particle to the entrance of 19S activator (middle). Structures are produced by PyMOL. Schematic drawing of the 26S proteasome indicates the approximate locations of the enzymatic activities and binding platforms on the 19S activator cap (right). α (light red) and β (dark red) subunits of the 20S particle, ATPase domain (dark blue) and OB domain (light blue) of ATPase subunits, backbone of lid sub particle (yellow), docking subunits Rpn1 (light purple) and Rpn2 (dark purple), ubiquitin receptors Rpn10 (light green) and Rpn13 (dark green), and DUB metallo-protease subunit Rpn11 (sky blue).

Figure 2

Figure 2

Schematic representation of the degradation cycle of the ubiquitin proteasome system. Proteins are targeted to the proteasome by a two-part degradation signal or degron. It consists of an intrinsically disordered region within the substrate and a reversibly attached polyubiquitin tag (Ub_n_). Polyubiquitin tag is attached by E1-E2-E3 ubiquitination cascade and this process can be reversed by DUBs (top left). The proteasome recognizes its substrates at the ubiquitin tag through ubiquitin receptors (Rpn10 and Rpn13; green) (top) and initiates degradation at the unstructured region (right). Once the proteasome has engaged its substrate, it unravels the protein by translocating it into a central cavity in the core particle, where the protein is proteolysed sequentially (bottom). Polyubiquitin tag is cleaved off by the intrinsic DUB Rpn11 (skyblue) immediately before the degradation.

Figure 3

Figure 3

The proteasome recognizes substrates in three different modes; ubiquitin-dependent (left), adapter-mediated (middle), and ubiquitin-independent (right) modes. In all three, an intrinsically disordered region in the substrate is recognized by the ATPase motor to allow the proteasome to initiate degradation. This aspect of proteasomal degradation resembles the targeting mechanisms predominant with the bacterial and archaeal analogues of the proteasome. Ubiquitin tags can be either recognized by the two intrinsic proteasome receptors Rpn10 and Rpn13 (left), or by non-stoichiometric proteasome subunits that serve as substrate adaptors such as UbL-UBA proteins (middle). The UbL-UBA proteins might bind substrates by themselves (second right) or together with the intrinsic substrate receptors (second left), which facilitate degradation of various substrates by positioning the disordered region properly. Finally, some substrates may be recognized only by their initiation sites.

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