Science https://doi.org/10.1126/science.aap8236 (2018)

The BTB protein domain functions as an interaction module, enabling self-association as a homodimer or interaction with non-BTB proteins within ubiquitin ligase or transcription factor complexes. While BTB domain proteins have the potential to form complexes with other BTB proteins, very few of these complexes, which are likely inactive, are detected in cells. To explore this discrepancy, Mena et al. generated artificial BTB heterodimers and observed interactions with the SCF E3 ligase adaptor FBXL17. In particular, FBXL17 interacted with specific residues in the BTB domain that were exposed in immature homodimers and BTB heterodimers but were buried in mature BTB homodimers. This interaction resulted in the ubiquitination and proteosomal degradation of aberrant BTB complexes while sparing mature BTB homodimers. MS analysis of endogenous BTB proteins in cells lacking FBXL17 revealed an increased abundance of aberrant complexes with other BTB proteins and an impaired ability to interact with their endogenous substrates. A similar phenotype was observed in Xenopus laevis embryos treated with a FBXL17 morpholino, with defects in neuronal and neuron crest differentiation. Overall, these findings reveal a unique quality control system that specifically prevents accumulation of protein complexes of aberrant composition, rather than detecting protein misfolding.