Molecular organization of the cullin E3 ligase adaptor KCTD11

Correale, Stefania; Pirone, Luciano; Marcotullio, Lucia Di; Smaele, Enrico De; Greco, Azzura; Mazzà, Daniela; Moretti, Marta; Alterio, Vincenzo; Vitagliano, Luigi; Gaetano, Sonia Di; Gulino, Alberto; Pedone, Emilia

doi:10.1016/j.biochi.2010.12.014

Cited by 51 publications

(66 citation statements)

References 28 publications

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“…Multiple steps in AP-2 expression and function might be inhibited by KCTD15. Using HEK293T cells, we asked first whether KCTD15 reduces expression of AP-2α, the rationale being that some KCTD proteins are cofactors of ubiquitin ligases, leading to degradation of their substrates (36,37). Eliminating this possibility we found that the level of AP-2α protein in the cell was not affected by KCTD15 (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…BTB domain-containing proteins were classified into four subgroups with variable properties, yet the basic folding structure of BTB domains remains similar (48). The Kctd factors belong to the T1 subfamily of BTB domain-containing proteins that are believed to assemble as tetramers (48), and a tetrameric form has been suggested for KCTD11 (37). However, the only structure solved for a family member, KCTD5, shows a pentameric assembly, albeit with maintenance of the common BTB fold (49).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2

Zarelli

Dawid

2013

Proc. Natl. Acad. Sci. U.S.A.

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The neural crest develops in vertebrate embryos within a discrete domain at the neural plate boundary and eventually gives rise to a migrating population of cells that differentiate into a multitude of derivatives. We have shown that the broad-complex, tramtrack and bric a brac (BTB) domain-containing factor potassium channel tetramerization domain containing 15 (Kctd15) inhibits neural crest formation, and we proposed that its function is to delimit the neural crest domain. Here we report that Kctd15 is a highly effective inhibitor of transcription factor activating enhancer binding protein 2 (AP-2) in zebrafish embryos and in human cells; AP-2 is known to be critical for several steps of neural crest development. Kctd15 interacts with AP-2α but does not interfere with its nuclear localization or binding to cognate sites in the genome. Kctd15 binds specifically to the activation domain of AP-2α and efficiently inhibits transcriptional activation by a hybrid protein composed of the regulatory protein Gal4 DNA binding and AP-2α activation domains. Mutation of one proline residue in the activation domain to an alanine (P59A) yields a protein that is highly active but largely insensitive to Kctd15. These results indicate that Kctd15 acts in the embryo at least in part by specifically binding to the activation domain of AP-2α, thereby blocking the function of this critical factor in the neural crest induction hierarchy.neural plate border | Tfap2 | FoxD3 | transcriptional regulation T he neural crest (NC) is a uniquely vertebrate migratory cell population that gives rise to multiple derivatives, including craniofacial skeleton, peripheral nervous system, and melanocytes, whereas the neural plate border is a broad competence domain that contains progenitors for the NC and placodes (1, 2). When exposed to appropriate stimuli, progenitors acquire NC fate and express multiple factors that activate downstream genes (3-8), and several signaling cascades, including bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt), FGF, retinoic acid, and Notch are vital in NC induction (9-12). Deficits in NC development are responsible for many birth defects (13-15), broadening the interest in this system.An important regulatory component in NC development is transcription factor AP-2, a target of Wnt signaling (16-21). The AP-2 family contains five members (22), among which AP-2α, -β, and -γ act in NC formation. After dimerization, AP-2 binds to DNA at sites with the consensus sequence 5′-GCCNNNGGC-3′, affecting genes in a broad range of biological processes (22-27). AP-2 can be divided into two broad regions: the N-terminal part containing the transactivation domain (AD) and the C-terminal region harboring the DNA-binding domain (DBD) that also mediates dimerization (22,24). In zebrafish and Xenopus embryos, AP-2 is expressed in the NC anlage and has a role in NC formation (20,23,28,29). In zebrafish AP-2α is encoded by tfap2a, and lockjaw and montblanc mutations in this gene exhibit defects in NC deriva...

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2

Zarelli

Dawid

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…We show that in mHypoE-N25/2 cells mouse AP-2β and Kctd15, both directly interact with the sumoylation enzyme Ube2i. It is possible that Twz/Kctd15 acts like a scaffold where TfAP-2/AP-2β is either sumoylated or ubiquitinated, as many KCTD family members also interact with the ubiquitination apparatus [43], [44]. This post-translational modification might be required for TfAP-2/AP-2β activation.…”

Section: Discussionmentioning

confidence: 99%

Obesity-Linked Homologues TfAP-2 and Twz Establish Meal Frequency in Drosophila melanogaster

et al. 2014

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In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.

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“…As a hallmark of the KCTD family the N terminus of KCTD3 harbors a BTB motif. BTB motifs are found in numerous proteins with diverse functions including transcription repression (50), cytoskeleton regulation (51), and protein ubiquitination/degradation (52,53). BTB motifs can interact with non-BTB proteins but can also self-associate.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of Hyperpolarization-activated Cyclic Nucleotide-gated Channel 3 (HCN3) by Specific Interaction with K+ Channel Tetramerization Domain-containing Protein 3 (KCTD3)

Cao-Ehlker

Zong²,

Hammelmann³

et al. 2013

Journal of Biological Chemistry

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Background: HCN channels are key regulators of neuronal excitability. Results: We identify KCTD3 as a protein that specifically interacts with HCN3 in brain and up-regulates cell surface expression of this channel. Conclusion: KCTD3 is a novel accessory subunit of neuronal HCN3 channels. Significance: The identification of KCTD3 is an important step toward achieving a better understanding of the in vivo role of HCN3.

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Molecular organization of the cullin E3 ligase adaptor KCTD11

Cited by 51 publications

References 28 publications

Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2

Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2

Obesity-Linked Homologues TfAP-2 and Twz Establish Meal Frequency in Drosophila melanogaster

Up-regulation of Hyperpolarization-activated Cyclic Nucleotide-gated Channel 3 (HCN3) by Specific Interaction with K+ Channel Tetramerization Domain-containing Protein 3 (KCTD3)

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