Programmed destruction of regulatory proteins through the ubiquitin–proteasome system is a widely used mechanism for controlling signalling pathways^,. Cullins are proteins that function as scaffolds for modular ubiquitin ligases typified by the SCF (Skp1–Cul1–F-box) complex^,,. The substrate selectivity of these E3 ligases is dictated by a specificity module that binds cullins. In the SCF complex, this module is composed of Skp1, which binds directly to Cul1, and a member of the F-box family of proteins^,,,. F-box proteins bind Skp1 through the F-box motif, and substrates by means of carboxy-terminal protein interaction domains^,,. Similarly, Cul2 and Cul5 interact with BC-box-containing specificity factors through the Skp1-like protein elongin C. Cul3 is required for embryonic development in mammals and Caenorhabditis elegans^,, but its specificity module is unknown. Here we report the identification of a large family of BTB-domain proteins as substrate-specific adaptors for C. elegans CUL-3. Biochemical studies using the BTB protein MEL-26 and its genetic target MEI-1 (refs , ) indicate that BTB proteins merge the functional properties of Skp1 and F-box proteins into a single polypeptide.