San1 is a yeast ubiquitin ligase and central component of protein quality control (PQC) degradation in the nucleus. San1 protects the nucleus from the deleterious effects of structurally abnormal proteins, and many substrates are toxic in its absence. San1 is remarkable for its capacity to target structurally diverse proteins for degradation while maintaining specificity for abnormal proteins. I postulate that these capabilities are conferred by San1's intrinsic disorder; aside from its RING domain, San1 has no known protein-protein interaction domains or tertiary structure. Instead, the N- and C-terminal regions of San1 contain long stretches of disordered residues with short, conserved sequences that likely undergo disorder-to-order transitions upon binding substrates. As these binding sites are positioned in disordered, inherently flexible regions, San1 is capable of adopting distinct conformations to bind each substrate. In light of this binding plasticity, San1 must recognize a feature in structurally abnormal proteins that distinguishes them from their normally folded counterparts.

I also observe that San1 recognizes exposed hydrophobicity in its substrates, and that San1 recognition is triggered by exposure of as few as five contiguous hydrophobic residues. I find that exposed hydrophobicity recognized by San1 can also cause aggregation and cellular toxicity. This observation underscores the fundamental protective role for San1 and PQC-mediated degradation.