Single Amino Acid Disease Mutations Act as Genetic Glues to Drive Neo-substrate Degradation

Disease-associated missense mutations are well known to affect protein turnover by either impairing substrate-ubiquitin ligase interactions or inducing misfolding-triggered protein clearance. Whether such mutations can drive gain-of-function in substrate-selective protein degradation remains under-explored. Here, we develop a tri-color global protein stability system to profile mutational effects across the intrinsically disordered regions (IDRs) of human transcription factors. Unexpectedly, we identify single amino acid substitutions that create functional short linear motif degrons to drive targeted protein degradation independently of protein quality control. These disease variants are exemplified by the gain of an FRY-like degron in GATA2, whose deficiency leads to impaired immune function. Structural analyses reveal that the substituted residue enables neomorphic interaction between the transcription factor and the KLHL15 E3 ligase by complementing their otherwise suboptimal interface. The prevalence of such glue-like mutations beyond transcription factors suggests that quasi-degrons are widespread in protein IDRs and can be functionalized by simple mutations, a finding that may inform the rational discovery of molecular glue degraders.