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The KCTD Family of Proteins: Structure, Function, Disease Relevance Zhepeng Liu1†, Yaqian Xiang2† and Guihong Sun1*

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The KCTD Family of Proteins: Structure, Function, Disease Relevance Zhepeng Liu1†, Yaqian Xiang2† and Guihong Sun1* Liu et al. Cell & Bioscience 2013, 3:45 http://www.cellandbioscience.com/content/3/1/45 Cell & Bioscience REVIEW Open Access The KCTD family of proteins: structure, function, disease relevance Zhepeng Liu1†, Yaqian Xiang2† and Guihong Sun1* Abstract The family of potassium channel tetramerizationdomain (KCTD) proteins consists of 26 members with mostly unknown functions. The name of the protein family is due to the sequence similarity between the conserved N-terminal region of KCTD proteins and the tetramerization domain in some voltage-gated potassium channels. Dozens of publications suggest that KCTD proteins have roles in various biological processes and diseases. In this review, we summarize the character of Bric-a-brack,Tram-track, Broad complex(BTB) of KCTD proteins, their roles in the ubiquitination pathway, and the roles of KCTD mutants in diseases. Furthermore, we review potential downstream signaling pathways and discuss future studies that should be performed. Keywords: KCTD, BTB domain, Adaptor Introduction BTB domain and homology between KCTD family members The human potassium (K+) channel tetramerization The human genome includes approximately 400 BTB domain (KCTD)family of proteins consists of 26 mem- domain-containing proteins. The BTB domain is a highly bers that share sequence similarity with the cytoplasmic conserved motif of about 100 amino acids and can be + domain of voltage-gated K channels(Kv channels) [1-3]. found at the N-terminusof C2H2-type zinc-finger tran- The KCTD proteins have relatively conserved N-terminal scription factors and in some actin-binding proteins [11]. domains and variable C-termini. Comparative analyses of BTB domain-containing proteins include transcription the conserved N-terminal sequence suggest the presence factors, oncogenic proteins, ion channel proteins, and of a common Bric-a-brack,Tram-track, Broad complex KCTD proteins [2,12-14]. Many BTB domain-containing (BTB) domain, which is also known as the POZ domain. proteins contain one or two additional domains, such as The BTB domain is a versatile protein-protein interaction kelch repeats, zinc-finger domains, FYVE (Fab1, YOTB, motif that facilitates homodimerization or heterodimeriza- Vac1, and EEA1) fingers which is a novel zinc finger-like tion. A variety of functions have been identified for the domain found in several proteins involved in membrane BTB domain-containing KCTD proteins. These functions trafficking, or ankyrin repeats [15]. These special domains include transcriptional repression [4,5], cytoskeleton regu- provide unique characteristics and functions to the BTB lation [6], tetramerization and gating of ion channels [7,8], proteins. The BTB domain facilitates protein-protein and interaction with the cullin E3 (Cul3) ubiquitin ligase interactions between KCTD proteins to allow self- complex [9,10]. In this review, we will summarize the assembly or with non-BTB-domain-containing proteins homology between KCTD family members and some of to promote oligomerization [15]. The X-ray crystal the key features of KCTD proteins. We will also discuss structure of KCTD5 also revealed assemblies of five the roles of mutant KCTDs in disease. subunits while tetramers were anticipated [16]. A variety of functional roles of KCTD proteins have been identified by different signal pathways, including sonic hedgehog (Shh) [17-19], Wnt/beta-catenin [20], FGF [1], and GABA signaling [21-24]. Alignment of the amino acids in the po- * Correspondence: [email protected] tassium tetramerization domains of all known KCTD pro- †Equal contributors 1School of Basic Medical Sciences, Wuhan University, Wuhan 430072, teins demonstrates that most KCTD proteins can be People’s Republic of China divided into seven groups by amino acid sequences. Full list of author information is available at the end of the article © 2013 Liu et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. Cell & Bioscience 2013, 3:45 Page 2 of 5 http://www.cellandbioscience.com/content/3/1/45 The A-group contains KCTD9, KCTD17, KCTD 5, and successful ubiquitination of substrate proteins [26]. Cul3 KCTD 2. The B-group contains KCTD10, KCTD13, and is one of seven human cullin proteins (Cul1,Cul2,Cul3, TNFAIP1. The C-group contains KCTD7 and KCTD14. Cul4A,Cul4B,Cul5, and Cul7). Most cullins form com- The D-group contains KCTD8, KCTD12, and KCTD16. plexes with substrate proteins by interacting with the BTB The E-group contains KCTD11, KCTD21, and KCTD6. domains of adaptor proteins [3]. Thus, the BTB domain is Members of the F-group include KCTD1 and KCTD15. important for the process of ubiquitination and protein And the final group is the G-group, which contains degradation. Ubiquitination involves a three-step enzy- KCTD3 and SHKBP1 and BTB10. KCTD20, KCTD18, matic cascade, which is initially activated by ubiquitin- KCTD19, and KCTD4 do not belong to these seven activating enzyme(E1). The substrate is then transferred to groups (Figure 1). The evolutionary tree of the KCTD ubiquitin-conjugating enzyme(E2) and is finally linked family proteins is similar to the group that Skoblov M with ubiquitin ligase(E3) [27]. Various cellular functions, et al. built [25]. We also suggest that homologous KCTD including cell proliferation, differentiation, apoptosis, and members may share similar functional roles in prolifera- protein transport, involve protein ubiquitination and de- tion, transcription, protein degradation, regulation of G- ubiquitination [28]. Bioinformatics and mutagenesis ana- protein coupled receptors and other molecular or bio- lyses have demonstrated that the best-characterized mem- logical processes. ber of the KCTD family, KCTD11/REN, is expressed as two alternative variants, sKCTD11 and lKCTD11. Despite KCTD proteins as adaptor molecules the fact that both variants possess a BTB domain in the BTB-domain-containing KCTD proteins may act as adap- N-terminus, only the lKCTD11 form has a complete tors for interactions between the Cul3 ubiquitin ligase and BTB domain. Intriguingly, this has not disturbed the its substrates. Thus, BTB KCTD proteins may facilitate cul3-binding activity of sKCTD11. KCTD11/REN also Figure 1 A paralogues tree of the KCTD family proteins as cullin ligase adaptor and their substrate. Left: A paralogues tree built using entire amino acid sequences of the KCTD family proteins; Right: the family of KCTD proteins corresponding to cullin and their substrate. Liu et al. Cell & Bioscience 2013, 3:45 Page 3 of 5 http://www.cellandbioscience.com/content/3/1/45 mediates histone deacetylase (HDAC1) ubiquitination and diseases. For example, a homozygous mutation (R99X) in degradation via cullin binding, resulting in reduced Hh/ exon 2 of KCTD7 has been described in progressive myo- Gli signaling [18]. The KCTD21andKCTD6 have also clonic epilepsy (PME) [37]. A second homozygous mis- been found to have the same features as KCTD11 [29]. sense mutation (R94W) in exon 2 of KCTD7 has also Thus, KCTD21 and KCTD6 may also facilitate protein been found in PME [38]. In addition, a heterozygous mis- degradation and reduced cellular signaling due to asso- sense mutation (R84W) and a large heterozygous deletion ciations with ubiquitin ligases. KCTD5 and KCTD7 have of exons 3 and 4 of KCTD7 have also been reported in pa- also been shown to function as substrate-specific adaptors tients with PME [30,31]. Allelic deletion of human KCTD11 for cullin3-based E3 ligases [3,30,31]. In addition, KCTD7 at chromosomal location 17p13.2 has been found in me- has been shown to increase potassium conductance due dulloblastoma [19,39]. In addition, gene copy number to increased proteasome degradation of an unidentified variants (CNVs) of KCTD13 mapping to chromosomal lo- substrate [30]. Thus, several members of the KCTD family cation 16p11.2 are considered to be major genetic causes function as critical adaptor molecules for ubiquitin- of macrocephaly and microcephaly. Overexpression of mediated protein degradation. This function ultimately KCTD13 induces microcephaly, whereas suppression of results in the modulation of important downstream sig- the same locus results in a macrocephalic phenotype [40]. naling pathways and biological processes. As can be seen Missense mutations in KCTD1occur in Scalp-ear-nipple from Figure 1, cullin is fairly widely interaction with the (SEN) syndrome [41]. Single nucleotide polymorphisms family of KCTD proteins. In the future, this novel sub- (SNPs) of KCTD10 (i5642G- > C and V206VT- > C) are strate of KCTD will help to understand the function of associated with altered concentrations of HDL cholesterol, the complex of CUL3 –BTB. particularly in subjects with high levels of carbohydrate in- take [42]. KCTD mutants affect proliferation, differenti- KCTDs and disease ation, apoptosis, and metabolism in different tissues. For KCTD proteins have essential roles in proliferation, differ- example, the CNVs of KCTD13 affect the balance of pro- entiation, apoptosis, and metabolism. Improper regulation liferation and apoptosis in neuronal progenitor cells. In of KCTD genes has been associated with various diseases,
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