Last month, the Nobel Prize in Chemistry 2004 was awarded in Stockholm, Sweden. And, in this issue, you can read about the historical discoveries concerning regulated protein degradation that resulted in Aaron Ciechanover, Avram Hershko and Irwin Rose being awarded this Nobel Prize. As Aaron Ciechanover discusses in a Timeline article on page 79, protein components of the body were viewed as essentially stable constituents before the 1940s. However, the finding that these proteins are turned over extensively, and the discovery of the lysosome, led to the proposal that protein degradation occurs in this organelle. Yet, experimental evidence showed that non-lysosomal pathways have an important role in intracellular proteolysis, and the discovery of the ubiquitin–proteasome system resolved this mystery.

On page 9, also on the theme of ubiquitylation, Matthew D. Petroski and Raymond J. Deshaies review cullin–RING complexes — the largest known class of ubiquitin ligases. These complexes have a wide range of substrate-receptor subunits, so it is possible that there are hundreds of distinct cullin–RING ubiquitin ligases in eukaryotic cells. These enzymes are therefore key mediators of post-translational protein regulation and, although there is a great compositional and functional diversity, the authors propose that these enzymes can be characterized by a set of general principles.

Finally, a Highlight article on page 7 describes a recent Nature Methods paper by Michel Bouvier and colleagues on a new technique for detecting in situ changes in protein ubiquitylation. Despite a growing interest in ubiquitylation, a tool for studying the dynamics of this process has been lacking, and this new technique — which is based on bioluminescence resonance energy transfer — allows the dynamics of this modification to be monitored in living cells and in real time.