Targeting of protein ubiquitination by BTB–Cullin 3–Roc1 ubiquitin ligases

Furukawa, Megumi; He, Yizhou Joseph; Borchers, Christoph H.; Xiong, Yue

doi:10.1038/ncb1056

Cited by 396 publications

(438 citation statements)

References 30 publications

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“…BTB domain proteins have recently been shown to function as substrate receptors for CDL3 ubiquitin ligases (Furukawa et al, 2003;Geyer et al, 2003;Pintard et al, 2003;Xu et al, 2003;Zhang et al, 2004). The BTB domain of this new class of substrate receptor (e.g., MEL-26) interacts with the Cullin repeats of Cul3, analogous to the manner by which Skp1 interacts with Cul1 in the CDL1/SCF complex.…”

Section: Kel-8 Is a Substrate Receptor For Cdl3mentioning

confidence: 99%

KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

Schaefer

Rongo

2006

MBoC

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The regulated localization of ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs) to synapses is an important component of synaptic signaling and plasticity. Regulated ubiquitination and endocytosis determine the synaptic levels of AMPARs, but it is unclear which factors conduct these processes. To identify genes that regulate AMPAR synaptic abundance, we screened for mutants that accumulate high synaptic levels of the AMPAR subunit GLR-1 in Caenorhabditis elegans. GLR-1 is localized to postsynaptic clusters, and mutants for the BTB-Kelch protein KEL-8 have increased GLR-1 levels at clusters, whereas the levels and localization of other synaptic proteins seem normal. KEL-8 is a neuronal protein and is localized to sites adjacent to GLR-1 postsynaptic clusters along the ventral cord neurites. KEL-8 is required for the ubiquitin-mediated turnover of GLR-1 subunits, and kel-8 mutants show an increased frequency of spontaneous reversals in locomotion, suggesting increased levels of GLR-1 are present at synapses. KEL-8 binds to CUL-3, a Cullin 3 ubiquitin ligase subunit that we also find mediates GLR-1 turnover. Our findings indicate that KEL-8 is a substrate receptor for Cullin 3 ubiquitin ligases that is required for the proteolysis of GLR-1 receptors and suggest a novel postmitotic role in neurons for Kelch/CUL3 ubiquitin ligases. INTRODUCTIONGlutamate is the most abundant excitatory neurotransmitter in the brain, and glutamatergic synapses play a critical role in learning, memory, and developmental plasticity of the central nervous system (Meldrum, 2000). Ionotropic glutamate receptors (GluRs) receive and transduce glutamatergic signals on the postsynaptic face of synapses, where these multitransmembrane spanning proteins assemble into tetrameric glutamate-gated channels of differing subunit composition (Hollmann and Heinemann, 1994;Dingledine et al., 1999). The regulation of these receptors, the ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) type in particular, is a critical mechanism by which neurons modulate synaptic strength (Bredt and Nicoll, 2003;Malenka, 2003;Malinow, 2003;Sheng and Hyoung Lee, 2003). In addition, GluRs play a role in several diseases of the nervous system, ranging from neurodegeneration to drug addiction and schizophrenia (Tzschentke, 2002;Mattson, 2003;Moghaddam, 2003;Aarts and Tymianski, 2004). To better understand how AMPA-type GluRs (AMPARs) function in the nervous system, it is essential to determine how the synaptic level and activity of AMPARs are regulated.AMPAR synaptic levels are controlled by proteins that interact with signaling elements on the carboxy-terminal tail sequences that are exposed to the cytosol (Dong et al., 1997;Rongo et al., 1998;Song et al., 1998;Srivastava et al., 1998;Xia et al., 1999;Sans et al., 2001). Although some of the tail sequence signaling elements function to maintain high levels of AMPARs at the synapse, other signaling elements recruit factors that result in the ubiquitination, endocytosis, ...

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Section: Kel-8 Is a Substrate Receptor For Cdl3mentioning

confidence: 99%

KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

Schaefer

Rongo

2006

MBoC

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“…Plasmids expressing human CUL4A, DDB1, and CDT1 were as previously described (Ohta et al 1999;Liu et al 2002;Furukawa et al 2003;Hu et al 2004). Plasmids expressing DDB2, CSA, and all other WD40 proteins were produced by amplifying cDNA from either human HeLa or thymus (kind gift of Dr. Lishan Su, University of North Carolina, Chapel Hill, NC) cDNA libraries and subcloning into pcDNA3-based mammalian expression vectors.…”

Section: Plasmids Cell Culture and Cell Transfectionmentioning

confidence: 99%

“…VHL and SOCS proteins, via their additional protein-protein interaction modules, target various substrates differentially to the CUL2-ROC1 or CUL5-ROC2 catalytic cores (Kamura et al 1998(Kamura et al , 2001(Kamura et al , 2004Stebbins et al 1999;Zhang et al 1999). Omitting a linker, CUL3 utilizes its N-terminal domain to bind to proteins with a conserved 100-residue protein motif known as a BTB domain, which, via additional protein-protein interaction domains, then target various substrates to the CUL3-ROC1 catalytic core (Furukawa et al 2003;Geyer et al 2003;Pintard et al 2003;Xu et al 2003). The presence of multiple substrate receptors-mammals express >60 F-box, 40 SOCS, and 200 BTB proteins-suggests that cullins may form the largest family of E3 ligase complexes and control the ubiquitination of a wide variety of substrates.…”

mentioning

confidence: 99%

DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4–ROC1 ubiquitin ligases

He¹,

McCall²,

et al. 2006

Genes Dev.

Self Cite

295

344

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Cullins assemble the largest family of ubiquitin ligases by binding with ROC1 and various substrate receptors. CUL4 function is linked with many cellular processes, but its substrate-recruiting mechanism remains elusive. We identified a protein motif, the DWD box (DDB1-binding WD40 protein), and demonstrated the binding of 15 DWD proteins with DDB1-CUL4A. We provide evidence supporting the critical function of the DWD box and DDB1's role as the linker mediating DWD protein association with CUL4A. A database search predicts that about one-third of WD40 proteins, 90 in humans, contain the DWD box, suggesting a potentially large number of DWD-DDB1-CUL4-ROC1 E3 ligases. The ubiquitin-proteasome pathway regulates the concentration and conformation of many cellular proteins in response to changes in physiological conditions. This pathway consists of a cascade of three activities performed by E1 (ubiquitin-activating), E2 (ubiquitin-conjugating), and E3 (ubiquitin ligase) enzymes (Hochstrasser 1996;King et al. 1996;Hershko and Ciechanover 1998). A critical step in this process is how individual protein substrates are recruited to specific E3 ligases. The RING family represents the major family of E3 ligases. Members either contain an intrinsic RING finger domain (as in MDM2 and BRCA1) or bind in trans with a small RING finger protein, such as ROC1 (also known as Rbx1 and Hrt1) by the cullins, to recruit and activate an E2 (Jackson et al. 2000;Petroski and Deshaies 2005).A remarkable aspect of cullin E3 ligases is that each cullin can assemble into many distinct cullin-RING-dependent ligases (CRLs) by interacting with a conserved motif present in multiple proteins (Petroski and Deshaies 2005). To recruit specific substrates, CUL1 utilizes an N-terminal domain to bind with a linker protein, SKP1 (Feldman et al. 1997;Skowyra et al. 1997;, which does not interact with other cullins (Michel and Xiong 1998). SKP1 uses a separate domain to bind with a conserved protein motif, the F box, which, via its additional protein-protein interaction modules, recruits various substrates, often phosphorylated, to the CUL1-ROC1 catalytic core. To bring specific substrates to CUL2-and CUL5-dependent ligases, a heterodimeric linker complex containing elongins B and C binds simultaneously to an analogous N-terminal domain in CUL2 and CUL5 and to two similar protein motifs, the VHL box and SOCS box. VHL and SOCS proteins, via their additional protein-protein interaction modules, target various substrates differentially to the CUL2-ROC1 or CUL5-ROC2 catalytic cores (Kamura et al. 1998(Kamura et al. , 2001(Kamura et al. , 2004Stebbins et al. 1999;Zhang et al. 1999). Omitting a linker, CUL3 utilizes its N-terminal domain to bind to proteins with a conserved 100-residue protein motif known as a BTB domain, which, via additional protein-protein interaction domains, then target various substrates to the CUL3-ROC1 catalytic core (Furukawa et al. 2003;Geyer et al. 2003;Pintard et al. 2003;Xu et al. 2003). The presence of multiple substrate receptors-...

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“…Rather than using two proteins to provide adaptor and recognition functions, CUL3 complexes utilize proteins in which the two functions have coalesced. These proteins contain BTB (Broad complex Tramtrack, Bric-a-brac) domains that bind CUL3 and either Kelch or MATH domains to capture substrates (21)(22)(23)(24). Keap1 contains an N-terminus BTB domain and a C-terminus Kelch domain (14).…”

Section: Introductionmentioning

confidence: 99%

Covalent Modification at Cys151 Dissociates the Electrophile Sensor Keap1 from the Ubiquitin Ligase CUL3

Rachakonda

Xiong

Sekhar

et al. 2008

Chem. Res. Toxicol.

184

170

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The regulation of cellular stress responses to electrophiles and oxidants is mediated by the transcription factor NF-E2-related factor 2 (Nrf2), which, in turn, is regulated by CUL-E3 (CUL3) ligase-mediated ubiquitylation. The Kelch-like ECH-associated protein 1 (Keap1) serves as an adapter between CUL3 and Nrf2. We used the model electrophile N-iodoacetyl-N-biotinylhexylenediamine (IAB) to define the relationship among the adduction of Keap1 cysteine residues, structure, and function. Exposure of Keap1 to IAB in Vitro was accompanied by progressive loss of protein secondary structure, as monitored by CD spectroscopy and a loss of the ability to associate with recombinant CUL3. Dissociation of Keap1 from CUL3 in Vitro was dependent upon C151 in Keap1. A quantitative mass spectrometry-based kinetic analysis of adduction in HEK293 cells expressing FLAG-Keap1 revealed that Cys151 was one of the most reactive residues in ViVo and that it was required for IAB-mediated dissociation of the Keap1-CUL3 interaction. These results demonstrate that Cys151 adduction confers a critical alkylation sensor function upon Keap1, making Keap1 unique among BTB CUL3 adapter proteins.

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Targeting of protein ubiquitination by BTB–Cullin 3–Roc1 ubiquitin ligases

Cited by 396 publications

References 30 publications

KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4–ROC1 ubiquitin ligases

Covalent Modification at Cys151 Dissociates the Electrophile Sensor Keap1 from the Ubiquitin Ligase CUL3

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