Diversity of degradation signals in the ubiquitin-proteasome system

Abstract

The ubiquitin-proteasome system degrades an enormous variety of proteins that contain specific degradation signals, or 'degrons'. Besides the degradation of regulatory proteins, almost every protein suffers from sporadic biosynthetic errors or misfolding. Such aberrant proteins can be recognized and rapidly degraded by cells. Structural and functional data on a handful of degrons allow several generalizations regarding their mechanism of action. We focus on different strategies of degron recognition by the ubiquitin system, and contrast regulatory degrons that are subject to signalling-dependent modification with those that are controlled by protein folding or assembly, as frequently occurs during protein quality control.

Figure 1. Mechanisms for activation of N-end rule pathway substrates

a| Type 1 (basic) and type 2 (hydrophobic) destabilizing residues of the N-end rule pathway are shown in a single letter code. b| Cleavage by endopeptidases can lead to the positioning of a destabilizing residue (X) at the N terminus of the truncated protein. c| Cleavage between Met and Cys by methionine aminopeptidase (indicated by a lightning bolt) can lead to protein destabilization when followed by addition of Arg, a type 1 destabilizing residue (see panel d). d| Modification of Asn to Asp (or Gln to Glu) by specific deamidases can lead to the addition of Arg by arginyltransferase (upper panel). Oxidation of the N-terminal Cys residue (marked by Asterisk) can similarly lead to protein arginylation and degradation (lower panel).

Figure 2. Structure of CycE phosphodegron bound to the F-box protein Fbw7

a| Overall architecture of the Skp1-Fbw7-CycE C-terminal phosphodegron (CycE^degC) complex, with the secondary structure elements of Skp1, F-box, and linker domains labelled. b| CycE^degC binds across the narrow face of the Fbw7 β-propeller structure. The two phosphorylated residues Trp380 and Ser384 are shown. The eight Fbw7 blades and the strands for one blade are labelled by numbers and letters, respectively.

Figure 3. Degrons in ER-associated degradation

a| Helical-wheel representation of a region (residues 18-36) of the yeast α2 Deg1 degron that is predicted to form part of a coiled-coil structure. Residues whose mutation inhibited Deg1-mediated proteolysis are marked in bold. b| A model for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) organization in the endoplasmic reticulum (ER) membrane. The sterol-sensing domain is marked in orange. c| 3D structure of the Man3GlcNAc2 oligosaccharide attached to Asn34 of RNase B. The β-1,4-linked dimer of glucosamine (chitobiose), which functions as a binding site for SCF^Fbs1, is marked in red.