The evolutionarily conserved BTB/POZ domain from the promyelocytic leukemia zinc finger (PLZF) oncoprotein mediates transcriptional repression through the recruitment of corepressor proteins containing histone deacetylases in acute promyelocytic leukemia. We have determined the 2.0 A crystal structure of the BTB/POZ domain from PLZF (PLZF-BTB/POZ), and have carried out biochemical analysis of PLZF-BTB/POZ harboring site-directed mutations to probe structure-function relationships. The structure reveals a novel alpha/beta homodimeric fold in which dimer interactions occur along two surfaces of the protein subunits. The conservation of BTB/POZ domain residues at the core of the protomers and at the dimer interface implies an analogous fold and dimerization mode for BTB/POZ domains from otherwise functionally unrelated proteins. Unexpectedly, the BTB/POZ domain forms dimer-dimer interactions in the crystals, suggesting a mode for higher-order protein oligomerization for BTB/POZ-mediated transcriptional repression. Biochemical characterization of PLZF-BTB/POZ harboring mutations in conserved residues involved in protein dimerization reveals that the integrity of the dimer interface is exquisitely sensitive to mutation and that dimer formation is required for wild-type levels of transcriptional repression. Interestingly, similar mutational analysis of residues within a pronounced protein cleft along the dimer interface, which had been implicated previously for interaction with corepressors, has negligible effects on dimerization or transcriptional repression. Together, these studies form a structure-function framework for understanding BTB/POZ-mediated oligomerization and transcriptional repression properties.
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