FBXW11
Encyclopedia
βTrCP2 is a protein
that in humans is encoded by the BTRC (beta-transducin repeat containing) gene
.
This gene encodes a member of the F-box protein
family which is characterized by an approximately 40 residue structural motif
, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin
protein ligase
complex called SCFs (Skp1-Cul1-F-box protein), which often, but not always, recognize substrates in a phosphorylation-dependent manner. F-box proteins are divided into 3 classes:
The protein encoded by FBXW11 belongs to the Fbxw class as, in addition to an F-box, this protein contains multiple WD40 repeats. This protein is homologous to Xenopus
βTrCP, yeast
Met30, Neurospora
Scon2 and Drosophila
Slimb. In mammals, in addition to βTrCP2, a paralog protein (called βTrCP1 or FBXW11
) also exists, but, so far, their functions appear redundant and indistinguishable.
viral protein to eliminate cellular CD4
by connecting it to the proteolytic machinery. Subsequently, βTrCP was shown to regulate multiple cellular processes by mediating the degradation of various targets. Cell cycle regulators constitute a major group of βTrCP substrates. During S phase, βTrCP keeps CDK1 in check by promoting the degradation of the phosphatase CDC25A, whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation. In early mitosis, βTrCP mediates the degradation of EMI1, an inhibitor of the APC/C
ubiquitin ligase complex, which is responsible for the anaphase-metaphase transition (by inducing the proteolysis of Securin) and mitotic exit (by driving the degradation of mitotic CDK1 activating cyclin subunits). Furthermore, βTrCP controls APC/C by targeting REST, thereby removing its transcriptional repression on MAD2, an essential component of the spindle assembly checkpoint that keeps APC/C inactive until all chromatids are attached to the spindle microtubles.
βTrCP has also emerged as an important player in protein translation, cell grow and survival. In response to mitogens, PDCD4, an inhibitor of the translation initiation factor eIF4A, is rapidly degraded in a βTrCP- and S6K1-dependent manner, allowing efficient protein translation and cell growth. βTrCP also cooperates with mTOR and CK1α to induce the degradation of DEPTOR (an mTOR inhibitor), thereby generating an auto-amplification loop to promote the full activation of mTOR. At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival.
βTrCP also associates with phosphorylated IkappaBalpha and beta-catenin
destruction motifs, probably functioning in multiple transcriptional programs by regulating the NF-kappaB and the WNT pathways.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the BTRC (beta-transducin repeat containing) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
This gene encodes a member of the F-box protein
F-box protein
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the proteasome....
family which is characterized by an approximately 40 residue structural motif
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
protein ligase
Ligase
In biochemistry, ligase is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group dependent to one of the larger molecules...
complex called SCFs (Skp1-Cul1-F-box protein), which often, but not always, recognize substrates in a phosphorylation-dependent manner. F-box proteins are divided into 3 classes:
- Fbxws containing WD40 repeatWD40 repeatThe WD40 repeat is a short structural motif of approximately 40 amino acids , often terminating in a tryptophan-aspartic acid dipeptide...
s, - Fbxls containing leucine-rich repeatLeucine-rich repeatA leucine-rich repeat is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine...
s, - and Fbxos containing either "other" protein-protein interaction modules or no recognizable motifs.
The protein encoded by FBXW11 belongs to the Fbxw class as, in addition to an F-box, this protein contains multiple WD40 repeats. This protein is homologous to Xenopus
Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
βTrCP, yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
Met30, Neurospora
Neurospora
Neurospora is a genus of Ascomycete fungi. The genus name, meaning "nerve spore" refers to the characteristic striations on the spores that resemble axons....
Scon2 and Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
Slimb. In mammals, in addition to βTrCP2, a paralog protein (called βTrCP1 or FBXW11
BTRC (gene)
F-box/WD repeat-containing protein 1A also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene....
) also exists, but, so far, their functions appear redundant and indistinguishable.
Discovery
Human βTrCP (referred to both βTrCP1 and βTrCP2) was originally identified as a cellular ubiquitin ligase that is bound by the HIV-1 VpuVpu
Vpu is a HIV gene.Vpu stands for "Viral Protein U". Vpu is involved in viral budding, enhancing virion release from the cell by counteracting BST2 . In the absence of vpu, tetherin binds to the viral envelope and ties it to the cell membrane and other viral particles, impeding release of the viral...
viral protein to eliminate cellular CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
by connecting it to the proteolytic machinery. Subsequently, βTrCP was shown to regulate multiple cellular processes by mediating the degradation of various targets. Cell cycle regulators constitute a major group of βTrCP substrates. During S phase, βTrCP keeps CDK1 in check by promoting the degradation of the phosphatase CDC25A, whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation. In early mitosis, βTrCP mediates the degradation of EMI1, an inhibitor of the APC/C
Anaphase-promoting complex
Anaphase-Promoting Complex, also called cyclosome , is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin and RING subunit much like SCF...
ubiquitin ligase complex, which is responsible for the anaphase-metaphase transition (by inducing the proteolysis of Securin) and mitotic exit (by driving the degradation of mitotic CDK1 activating cyclin subunits). Furthermore, βTrCP controls APC/C by targeting REST, thereby removing its transcriptional repression on MAD2, an essential component of the spindle assembly checkpoint that keeps APC/C inactive until all chromatids are attached to the spindle microtubles.
Functions
βTrCP plays important roles in regulating cell cycle checkpoints. In response to genotoxic stress, it contributes to turn off CDK1 activity by mediating the degradation of CDC25A in collaboration with Chk1, thereby preventing cell cycle progression before the completion of DNA repair. During recovery from DNA replication and DNA damage, βTrCP instead targets Claspin in a Plk1-dependent manner.βTrCP has also emerged as an important player in protein translation, cell grow and survival. In response to mitogens, PDCD4, an inhibitor of the translation initiation factor eIF4A, is rapidly degraded in a βTrCP- and S6K1-dependent manner, allowing efficient protein translation and cell growth. βTrCP also cooperates with mTOR and CK1α to induce the degradation of DEPTOR (an mTOR inhibitor), thereby generating an auto-amplification loop to promote the full activation of mTOR. At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival.
βTrCP also associates with phosphorylated IkappaBalpha and beta-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
destruction motifs, probably functioning in multiple transcriptional programs by regulating the NF-kappaB and the WNT pathways.
Interactions
BTRC (gene) has been shown to interact with:- FBXW11
- DLG1DLG1Disks large homolog 1 , also known as synapse-associated protein 97 or SAP97, is a protein that in humans is encoded by the SAP97 gene....
- IκBα
- NFKB2NFKB2Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the NFKB2 gene.-Interactions:NFKB2 has been shown to interact with NFKBIE, BCL3, MAP3K8, BTRC, RELA, RELB, NFKB1, REL and TSC22D3.-Further reading:...
- RELARELATranscription factor p65 is a protein that in humans is encoded by the RELA gene.-Interactions:RELA has been shown to interact with NFKBIB, ETHE1, NFKBIE, RFC1, TRIB3, CREB binding protein, Neutrophil cytosolic factor 1, Glucocorticoid receptor, MTPN, BRCA1, C-Fos, POU2F1, BTRC, TATA-binding...
- SKP1ASKP1AS-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the SKP1 gene.This gene encodes a protein that is a member of the SCF ubiquitin ligase protein complex. It binds to F-box proteins , such as cyclin F, S-phase kinase-associated protein 2, and other regulatory proteins...
- CDC34CDC34Ubiquitin-conjugating enzyme E2 R1 is a protein that in humans is encoded by the CDC34 gene.-Interactions:CDC34 has been shown to interact with CSNK2B, BTRC and CDK9.-Further reading:...
- CUL1CUL1Cullin 1, also known as CUL1, is a human protein and gene from cullin family.This protein plays an important role in protein degradation and protein ubiquitination....
- β-catenin
- WEE1Wee1Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe . It has a molecular mass of 96 kDa and it is a key regulator of cell cycle progression....
- EMI1
- Cdc25ACDC25ACell division cycle 25 homolog A , also known as CDC25A, is a mammalian gene.-Interactions:CDC25A has been shown to interact with ASK1, Epidermal growth factor receptor, C-Raf, CHEK1, Cyclin E1, PIM1 and YWHAB.-Further reading:...
- ClaspinCLSPNClaspin is a protein that in humans is encoded by the CLSPN gene.-Interactions:CLSPN has been shown to interact with USP7, CHEK1 and BRCA1.-Further reading:...
- RESTRestRest may refer to:* Leisure* Human relaxation* SleepRest may also refer to:* Rest , a pause in a piece of music* Rest , the relation between two observers* Rest , a 2008 album by Gregor Samsa...
- PDCD4PDCD4Programmed cell death protein 4 is a protein that in humans is encoded by the PDCD4 gene. It is one of the targets of an oncomiR, MIRN21.-Interactions:PDCD4 has been shown to interact with RPS13 and Ribosomal protein L5.-Further reading:...
- DEPTOR