Structural basis for dimerization quality control

Most quality control pathways target misfolded proteins to prevent toxic aggregation and neurodegeneration (1). Dimerization quality control (DQC) further improves proteostasis by eliminating complexes of aberrant composition (2), yet how it detects incorrect subunits is still unknown. Here, we provide structural insight into target selection by SCF(FBXL17), a DQC E3 ligase that ubiquitylates and helps degrade inactive heterodimers of BTB proteins, while sparing functional homodimers. We find that SCF(FBXL17) disrupts aberrant BTB dimers that fail to stabilize an intermolecular β-sheet around a highly divergent β-strand of the BTB domain. Complex dissociation allows SCF(FBXL17) to wrap around a single BTB domain for robust ubiquitylation. SCF(FBXL17) therefore probes both shape and complementarity of BTB domains, a mechanism that is well suited to establish quality control of complex composition for recurrent interaction modules.