Btbd6-dependent Plzf recruitment to Cul3 E3 ligase complexes through BTB domain heterodimerization

Abstract

The Cul3 adaptor Btbd6 plays crucial roles in neural development by driving the ubiquitin-dependent degradation of promyelocytic zinc finger transcription factor (Plzf). Btbd6 has conserved motifs, BTB-BACK-PHR, and by analogy with other BTB-BACK adaptors, might be expected to bind to Cul3 through the BTB-BACK domain, and to substrate through the PHR domain. However, we now present a mode of adaptor-substrate interaction through heterodimerisation between the normally homodimeric BTB domains of Btbd6 and Plzf. This heterodimerization appears to occur through monomer exchange that is detected only at or near physiological concentrations. The Btbd6-Plzf heterodimer thus formed assembles into a ternary complex with Cul3. In addition we show that the BTB and PHR domains of Btbd6 promote localisation in the nucleus and that the BACK domain contains a nuclear export signal. Our findings support a model whereby Btbd6 moves into and out of the nucleus, iteratively sweeping Plzf into the cytoplasm and enabling complex formation with Cul3 that presents Plzf for ubiquitination.\n\nHighlightsO_LIA general mechanism for recruitment of BTB domain-containing substrates by BTBdomain adaptors for the Cul3 E3 ligase complex\nC_LIO_LINuclear export of the Plzf/Btbd6 complex mediated by a NES within the Btbd6 BACK domain\nC_LIO_LICul3-dependent Plzf ubiquitylation through heterodimerisation of BTB domains on adaptor and substrate by monomer exchang\nC_LI