Aberrant complex formation by recurrent interaction modules, such as BTB domains, leucine zippers, or coiled coils, can disrupt signal transduction, yet whether cells detect and eliminate complexes of irregular composition is unknown. By searching for regulators of the BTB family, we discovered a quality control pathway that ensures functional dimerization [dimerization quality control (DQC)]. Key to this network is the E3 ligase SCF, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation. Underscoring the physiological importance of DQC, SCF is required for the differentiation, function, and survival of neural crest and neuronal cells. We conclude that metazoan organisms actively monitor BTB dimerization, and we predict that distinct E3 ligases similarly control complex formation by other recurrent domains.

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.

Highlights d CUL2 FEM1B recognizes reduced FNIP1 through two interface zinc ions d Zn 2+ is essential for reductive stress signaling d FNIP1 access to CUL2 FEM1B is gated by BEX protein pseudosubstrate inhibitors d Mutation of FEM1B and BEX deletion cause similar developmental syndromes