Molecular recognition of Cullin3 by KCTDs: Insights from experimental and computational investigations

Balasco, Nicole; Pirone, Luciano; Smaldone, Giovanni; Gaetano, Sonia Di; Esposito, Luciana; Pedone, Emilia; Vitagliano, Luigi

doi:10.1016/j.bbapap.2014.04.006

Cited by 33 publications

(62 citation statements)

References 42 publications

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“…These observations suggest that Kctd15 may affect the development of multiple cells and tissues in embryogenesis. The large number of genes affected by Kctd15 in our experiments further suggest that the molecular function of Kctd15 might be in the regulation of transcription rather than in other pathways as indicated for different members of the Kctd family (Balasco et al, 2014; Bayon et al, 2008; Canettieri et al, 2010; Chen et al, 2009; Correale et al, 2011). Our results provide a framework for future studies into the biological role of Kctd15.…”

Section: Discussionmentioning

confidence: 61%

“…BTB domains, also called POZ domains, are widely involved in protein-protein interactions (Perez-Torrado et al, 2006; Stogios et al, 2005), and thus it is not surprising that acting as adapters is perhaps the best-studied molecular function of Kctd proteins. Kctd5, Kctd6 and Kctd11 bind Cullin 3 and act as adapters mediating the interactions of E3 ubiquitin ligases with their substrates (Balasco et al, 2014; Bayon et al, 2008; Canettieri et al, 2010; Chen et al, 2009; Correale et al, 2011). While other Kctd proteins also have been reported to bind Cullin 3, this has been contradicted in recent work (Smaldone et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Genes regulated by potassium channel tetramerization domain containing 15 (Kctd15) in the developing neural crest

Wong¹,

Rebbert²,

Wang³

et al. 2016

Int. J. Dev. Biol.

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Neural crest (NC) development is controlled precisely by a regulatory network with multiple signaling pathways and the involvement of many genes. The integration and coordination of these factors are still incompletely understood. Overexpression of Wnt3a and the BMP antagonist Chordin in animal cap cells from Xenopus blastulae induces a large number of NC specific genes. We previously suggested that Potassium Channel Tetramerization Domain containing 15 (Kctd15) regulates NC formation by affecting Wnt signaling and the activity of transcription factor AP-2. In order to advance understanding of the function of Kctd15 during NC development, we performed DNA microarray assays in explants injected with Wnt3a and Chordin, and identify genes that are affected by overexpression of Kctd15. Among many genes identified we chose Duf domain containing protein 1(ddcp1), Platelet-Derived Growth Factor Receptor a (pdgfra), Complement factor properdin (cfp), Zinc Finger SWIM-Type Containing 5 (zswim5), and complement component 3 (C3) to examine their expression by whole mount in situ hybridization. Our work points to a possible role for Kctd15 in the regulation of NC formation and other steps in embryonic development.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Genes regulated by potassium channel tetramerization domain containing 15 (Kctd15) in the developing neural crest

Wong¹,

Rebbert²,

Wang³

et al. 2016

Int. J. Dev. Biol.

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“…Since co-expression of cullin3 enhanced the binding of full-length KCTD5 to ZNF711, we favor the hypothesis that a functional cullin3/KCTD5 complex mediates this ZNF711 protein stabilization. The interactions of KCTD proteins with cullin3 have been shown to induce changes in KCTD conformation [27], which may contribute to this enhanced binding of the substrate. With regard to the lack of cullin3/KCTD5 dependent polyubiquitylation of MCM7 it has to be noted that KCTD5 contains none of the substrate recognition domains such as zinc fingers, meprin and traf homology or Kelch shown to be required for substrate recognition in BTB proteins successfully characterized as cullin3 ubiquitin ligase adapters.…”

Section: Stabilization Of Znf711 After Kctd5 and Cullin3 Overexpressionmentioning

confidence: 99%

Interactions of cullin3/KCTD5 complexes with both cytoplasmic and nuclear proteins: Evidence for a role in protein stabilization

Rutz

Heilbronn

Weger

2015

Biochemical and Biophysical Research Communications

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“…The C-terminal region comprises 4-6 Kelch repeats arranged into a single β-propeller that captures the substrates for the C3RL complex; alternatively, these Kelch domains may also interact with actin filaments to regulate cytoskeleton organisation (5,(9)(10)(11)(14)(15)(16)(17)(18)(19). In cells, there are many BTB-domain-containing proteins conjugated with different substrate recognition domains and their interactions with various substrates and C3RL complexes are implicated in several cellular processes including protein degradation, transcriptional regulation (Keap1), the gating of voltage-gated potassium channels (KCTDs), and cytoskeleton modulation (KLHLs) (19)(20)(21)(22)(23)(24)(25). Apart from mimiviruses, poxviruses are the only family of viruses that make BTB domain-containing proteins (26)(27)(28)(29)(30).…”

mentioning

confidence: 99%

“…C3RLs are a family of multi-modular cullin-RING based E3 ubiquitin ligases that recruit substrates specifically via BTB-domain containing adaptor proteins (5,6). Cul3, the all-helical stalk-like scaffold subunit of C3RLs, interacts directly with BTB-domain-containing proteins via its N-terminal domain (6)(7)(8)13,24,33). The C-terminal domain of Cul3 interacts with the RING based E3 ligase protein to recruit the ubiquitin-loaded E2-conjugating enzyme for substrate ubiquitylation and is dispensable for binding to BTB-domain proteins (5,11,34).…”

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confidence: 99%

Molecular basis of Cul3 ubiquitin ligase subversion by vaccinia virus protein A55

Gao

Pallett

Croll

et al. 2018

Preprint

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BTB-Kelch proteins are substrate-specific adaptors for cullin-3 (Cul3) RING-box based E3 ubiquitin ligases, which mediate protein ubiquitylation leading to proteasomal degradation. Vaccinia virus encodes three BTB-Kelch proteins, namely A55, C2 and F3. Viruses lacking A55 or C2 demonstrate altered cytopathic effect in cultured cells and altered pathology in vivo. Previous studies show that the ectromelia virus orthologue of A55, EVM150, interacts with Cul3 in cells. We show that A55 binds directly to Cul3 via its N-terminal BTB-BACK domain, and together they form a 2:2 complex in solution. The crystal structure of the A55/Cul3 complex was solved to 2.8 Å resolution. The overall conformation and binding interfaces resemble those of the cellular BTB-BACK/Cul3 complex structures, despite low sequence similarity of A55 to cellular BTB-BACK proteins. Surprisingly, despite this structural similarity the affinity of Cul3 for A55 is significantly higher than for reported cellular BTB-BACK proteins. Detailed analysis of the binding interface suggests that I48 from A55 at the BTB/Cul3 interface is important for this high-affinity interaction and mutation at this site reduced the affinity by several orders of magnitude. I48 is conserved only in close orthologues of A55 from poxviruses, but not in C2, F3, or other poxvirus or cellular BTB-Kelch proteins. The high affinity interaction between A55 and Cul3 suggests that, in addition to directing the Cul3-RING E3 ligase complex to degrade cellular/viral target proteins that are normally unaffected, A55 may also sequester Cul3 from cellular adaptor proteins and thus protect substrates of these cellular adaptors from ubiquitination and degradation.1 The abbreviations used are: BACK, BTB and C-terminal Kelch; BTB, Bric-a-brac, Tramtrack and Broad-complex; BB, BTB-3-box-BACK domain; Cul3, cullin-3; C3RL, Cul3-RING based E3 ubiquitin ligase

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Molecular recognition of Cullin3 by KCTDs: Insights from experimental and computational investigations

Cited by 33 publications

References 42 publications

Genes regulated by potassium channel tetramerization domain containing 15 (Kctd15) in the developing neural crest

Genes regulated by potassium channel tetramerization domain containing 15 (Kctd15) in the developing neural crest

Interactions of cullin3/KCTD5 complexes with both cytoplasmic and nuclear proteins: Evidence for a role in protein stabilization

Molecular basis of Cul3 ubiquitin ligase subversion by vaccinia virus protein A55

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