Degron discovery: The hunt for the elusive dark matter of protein quality control

Proteins are in constant equilibrium between different folding states, some of which may be detrimental to cell survival. Consequently, all proteins are subjected to tight surveillance by means of coupling protein conformation to protein stability, a feat carried out by the protein quality control machinery. The folding state is reported to the degradation machinery, so we assume, through degradation signals, termed degrons, that when the time comes, dispose of their bearer to elimination. Yet, despite the conviction that degrons present in all proteins, there has been no efficient way to rationally predict what these elements look like, let alone to identify them within the eukaryotic proteome. Obviously, affecting the proteome but otherwise invisible, degrons remained a "dark matter" waiting to be revealed.

Acknowledging the lack of rational means to discover degrons, we have established an unbiased approach in yeast, where protein degradation rates are inversely coupled to cell growth. Applying high throughput sequencing, we have subsequently identified degrons within the entire yeast proteome, whose most distinctive quality control determinants are hydrophobic regions. We also found that the cellular compartment where a degron is expressed often dictates its activity, suggesting that compartment-specific E3 ligases have distinct recognition repertoires. Nevertheless, the initial screen did not reveal a link between specific degron properties and distinct recognition patterns of quality control E3 ligases. With these in mind, the degron discovery system has been adapted to identify compartment-specific and E3-specific degron repertoires. The new methodologies and findings will be discussed.