In general, every protein has the potential to undergo misfolding and therefore to become a substrate for ubiquitin-mediated degradation. However, what are the degradation signals (degrons) that the UPS recognizes as “misfolded” is largely unknown.

To address this fundamental issue we have previously established a unique high-throughput degron screen in yeast. Using growth assays, combined with deep sequencing, we measured a quantitative degradation potency for thousands of polypeptides in yeast simultaneously (Geffen et al., Mol Cell, 2016).

Recently, we developed an improved screen, using dual fluorescence markers, and combined it with a Machine-Learning approach, resulting in an algorithm, termed QCDPred, that predicts the presence of QCAP degrons in all eukaryotic proteins, from yeast to humans (Bashahreh et al., Nat Comms, 2022; Johansson et al., J Mol Biol, 2022). This study identified, for the first time, conserved degron features governing QCAP. From a broader perspective, we anticipate this work to be the first step toward a complete assessment of the mechanism of the recognition and sorting of misfolded proteins in health and disease.