The cullin protein family

Sarikas, Antonio; Hartmann, Thomas; Pan, Zhen‐Qiang

doi:10.1186/gb-2011-12-4-220

Cited by 420 publications

(411 citation statements)

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“…We note that BRWD3 (24) is the Drosophila homolog of the human WDR9 gene (25) (also known as BRWD1), and the mutation of BRWD3 in Drosophila is known as ramshackle (21). Several members of this family of proteins are known to function as substrate receptors for CRL4 E3 ligases (20,26). We first established that BRWD3 interacted with dCRY in yeast two hybrid in a light-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…Lightdependent binding of dCRY to BRWD3, along with the inhibition of light-dependent degradation of dCRY after BRWD3 knockdown, suggested that BRWD3 might function as a substrate receptor for a CRL4 E3 ligase in a manner similar to JET functioning as a substrate receptor for CRL1 E3 ligase (14). In CRL4 E3 ligases, DDB1 functions as a linker between the Cullin 4 scaffold and a WD40-protein substrate receptor (20,26). Indeed, when BRWD3 was expressed in human HEK293T cells and immunopurified, DDB1, CUL4A, CUL4B, and ROC1 copurified with it, indicating that BRWD3 is a substrate receptor for a CRL4 E3 ligase (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex

Öztürk

VanVickle-Chavez

Akileswaran

et al. 2013

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

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Cryptochrome (CRY) is the primary circadian photoreceptor in Drosophila. It resets the circadian clock by promoting lightinduced degradation of the clock proteins Timeless and Period, as well as its own proteolysis. The E3 ligases that ubiquitylate Timeless and Period before degradation are known and it is known that Drosophila (d) CRY is degraded by the ubiquitin-proteasome system as well. To identify the E3 ligase for dCRY we screened candidates in S2 cells by RNAi. Knockdown of each of the 25 putative F-box proteins identified by bioinformatics did not attenuate the light-induced degradation of dCRY. However, knockdown of a WD40 protein, Bromodomain and WD repeat domain containing 3 (Brwd3) (CG31132/Ramshackle) caused strong attenuation of dCRY degradation following light exposure. We found that BRWD3 functions as a Damage-specific DNA binding protein 1 (DDB1)-and CULLIN (CUL)4-associated factor in a Cullin4-RING Finger E3 Ligase (CRL4) that mediates light-dependent binding of dCRY to CUL4-ROC1-DDB1-BRWD3, inducing ubiquitylation of dCRY and its lightinduced degradation. Thus, this study identifies a light-activated E3 ligase complex essential for light-mediated CRY degradation in Drosophila cells.circadian rhythm | sensory flavoprotein | photocycle

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex

Öztürk

VanVickle-Chavez

Akileswaran

et al. 2013

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

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“…npg nucleus to target transcription factors and nucleotide excision repair proteins (reviewed in [6][7][8]). Moreover, in response to environmental toxins, the extreme N terminus of CUL4B binds to the aryl hydrocarbon receptor (AhR) to form a distinct E3 ligase that catalyzes the ubiquitination and degradation of the estrogen receptor, progesterone receptor, and AhR itself [15].…”

Section: Discussionmentioning

confidence: 99%

“…CUL4B is a member of the cullin-RING ubiquitin ligase (CRL) family, which is the largest E3 ligase subtype in mammals that controls a wide spectrum of cellular processes including cell cycle, DNA replication and repair, signaling, transcription, and embryonic development (reviewed in [6][7][8]). CRLs are multimeric E3 ligase complexes that assemble on the elongated cullin scaffold: the RING domain adaptor Rbx1/Roc1 recruits the E2 ubiquitin-conjugating enzyme and interacts with the C-terminal cullin homology domain, while the cullin N-terminus associates with a cullin-specific adaptor protein to recruit a large family of substrate receptors, each of which can bind multiple substrates.…”

Section: Introductionmentioning

confidence: 99%

Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis

Liu

Yin

et al. 2012

Cell Res

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Mutations of the CUL4B ubiquitin ligase gene are causally linked to syndromic X-linked mental retardation (XLMR). However, the pathogenic role of CUL4B mutations in neuronal and developmental defects is not understood. We have generated mice with targeted disruption of Cul4b, and observed embryonic lethality with pronounced growth inhibition and increased apoptosis in extra-embryonic tissues. Cul4b, but not its paralog Cul4a, is expressed at high levels in extra-embryonic tissues post implantation. Silencing of CUL4B expression in an extra-embryonic cell line resulted in the robust accumulation of the CUL4 substrate p21 Cip1/WAF and G2/M cell cycle arrest, which could be partially rescued by silencing of p21 Cip1/WAF . Epiblast-specific deletion of Cul4b prevented embryonic lethality and gave rise to viable Cul4b null mice. Therefore, while dispensable in the embryo proper, Cul4b performs an essential developmental role in the extra-embryonic tissues. Our study offers a strategy to generate viable Cul4b-deficient mice to model the potential neuronal and behavioral deficiencies of human CUL4B XLMR patients.

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“…Among the most extensively studied systems that produce K48-linked Ub chains is the SCF (Skp1-Cullin1-F-box) E3-directed ubiquitination. SCF is a member of the multisubunit Cullin-RING E3 Ub ligase (CRL) family, the largest of all E3s (2). CRL contains a tandem of a large scaffold protein [Cullin (CUL)] and a RING domain-containing protein (ROC1/Rbx1) that typically associates with an adaptor protein (such as Skp1) in complex with a substrate recognition protein (such as F-box protein).…”

mentioning

confidence: 99%

Pivotal role for the ubiquitin Y59-E51 loop in lysine 48 polyubiquitination

Chong¹,

Wu²,

Spratt

et al. 2014

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

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Lysine 48 (K48)-polyubiquitination is the predominant mechanism for mediating selective protein degradation, but the underlying molecular basis of selecting ubiquitin (Ub) K48 for linkage-specific chain synthesis remains elusive. Here, we present biochemical, structural, and cell-based evidence demonstrating a pivotal role for the Ub Y59-E51 loop in supporting K48-polyubiquitination. This loop is established by a hydrogen bond between Ub Y59's hydroxyl group and the backbone amide of Ub E51, as substantiated by NMR spectroscopic analysis. Loop residues Y59 and R54 are specifically required for the receptor activity enabling K48 to attack the donor Ub-E2 thiol ester in reconstituted ubiquitination catalyzed by Skp1-Cullin1-F-box (SCF) βTrCP E3 ligase and Cdc34 E2-conjugating enzyme. When introduced into mammalian cells, loop-disruptive mutant Ub R54A/Y59A diminished the production of K48-polyubiquitin chains. Importantly, conditional replacement of human endogenous Ub by Ub R54A/Y59A or Ub K48R yielded profound apoptosis at a similar extent, underscoring the global impact of the Ub Y59-E51 loop in cellular K48-polyubiquitination. Finally, disulfide cross-linking revealed interactions between the donor Ub-bound Cdc34 acidic loop and the Ub K48 site, as well as residues within the Y59-E51 loop, suggesting a mechanism in which the Ub Y59-E51 loop helps recruit the E2 acidic loop that aligns the receptor Ub K48 to the donor Ub for catalysis.receptor ubiquitin | E3 ubiquitin ligase | E2 ubiquitin-conjugating enzyme C entral to selective protein turnover by the 26S proteasome is the formation of homotypic lysine 48 (K48)-linked ubiquitin (Ub) chains that tag substrate proteins for degradation (1). Among the most extensively studied systems that produce K48-linked Ub chains is the SCF (Skp1-Cullin1-F-box) E3-directed ubiquitination. SCF is a member of the multisubunit Cullin-RING E3 Ub ligase (CRL) family, the largest of all E3s (2). CRL contains a tandem of a large scaffold protein [Cullin (CUL)] and a RING domain-containing protein (ROC1/Rbx1) that typically associates with an adaptor protein (such as Skp1) in complex with a substrate recognition protein (such as F-box protein). As such, the organization of CRL subunits positions the substrate receptor (such as the F-box protein) within the proximity of ROC1, which recruits an E2-conjugating enzyme that catalyzes the transfer of Ub to a bound substrate. In the SCF reconstitution system, K48-linked polyubiquitin chains on a substrate such as IκBα and β-catenin are produced in a two-step reaction. The E2 UbcH5c deposits the first Ub moiety, forming a substrate-Ub linkage, which is followed by repeated discharge of subsequent Ubs by E2 Cdc34 to form K48-specific Ub chains (3). Human Cdc34 contains a highly conserved charged acidic loop (residues 102-113) that participates in the elongation of K48 chains (4, 5). The current work addresses whether there are determinants on the Ub itself that dictate K48 linkage specificity and, moreover, how Cdc34 might recognize Ub K48. R...

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The cullin protein family

Cited by 420 publications

References 95 publications

Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex

Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex

Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis

Pivotal role for the ubiquitin Y59-E51 loop in lysine 48 polyubiquitination

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