The BTB (bric-a-brac, tramtrak and broad complex) ⁄ POZ (poxvirus zinc finger) domain is a proteinprotein interaction domain first described in several proteins of Drosophila melanogaster and poxvirus [1,2]. BTB ⁄ POZ domain-containing proteins constitute a diverse group of proteins involved in transcriptional repression, cytoskeletal regulation, and ion channel function [3]. More recently, some BTB proteins have been characterized as substrate-specific adaptors for cullin(CUL)3-based E3 ligases [4][5][6][7]. The BTB domain of these substrate-specific adaptors binds to CUL3, whereas additional domains in these polypeptides, such as zinc fingers, meprin and traf homology (MATH) domain, and Kelch repeats, work as substrate recognition domains. The first protein shown to be regulated by a CUL3 ligase was MEI-1 in Caenorhaditis elegans. This protein is part of the katanin-like microtubule severing complex [5,6] Potassium channel tetramerization domain (KCTD) proteins contain a bric-a-brac, tramtrak and broad complex (BTB) domain that is most similar to the tetramerization domain (T1) of voltage-gated potassium channels. Some BTB-domain-containing proteins have been shown recently to participate as substrate-specific adaptors in multimeric cullin E3 ligase reactions by recruiting proteins for ubiquitination and subsequent degradation by the proteasome. Twenty-two KCTD proteins have been found in the human genome, but their functions are largely unknown. In this study, we have characterized KCTD5, a new KCTD protein found in the cytosol of cultured cell lines. The expression of KCTD5 was upregulated post-transcriptionally in peripheral blood lymphocytes stimulated through the T-cell receptor. KCTD5 interacted specifically with cullin3, bound ubiquitinated proteins, and formed oligomers through its BTB domain. Analysis of the interaction with cullin3 showed that, in addition to the BTB domain, some amino acids in the N-terminus of KCTD5 are required for binding to cullin3. These findings suggest that KCTD5 is a substrate-specific adaptor for cullin3-based E3 ligases.Abbreviations AU, arbitrary unit; BTB, bric-a-brac, tramtrak and broad complex; CT, cycle threshold; CUL, cullin; GFP, green fluorescent protein; GST, glutathione S-transferase; HA, hemagglutinin; IL-2, interleukin-2; KCTD, potassium channel tetramerization domain; MATH, meprin and traf homology; PBL, peripheral blood lymphocyte; PHA, phytohemagglutinin; PMA, 4b-phorbol 12-myristate 13-acetate; POZ, poxvirus zinc finger; Ub, ubiquitin.