SCF complex
Encyclopedia
Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase
complex catalyzing the ubiquitin
ation of proteins destined for proteasomal
degradation. It has important roles in the ubiquitination of proteins involved in the cell cycle as well as having a role in the marking various other cellular proteins for destruction.
SCF contains three core subunits, and a number of less critical components:
Progression of eukaryotic cell cycle
is regulated through synthesis-degradation and phosphorylation-dephosphorylation of cell cycle regulating proteins. Two ubiquitin ligases are crucial in cell cycle. The anaphase-promoting complex or cyclosome (APC/C) controls metaphase
-anaphase
transition with its activator Cdc20
. Its activity is required for sister chromatids
separation. APC/C with another activator, Cdh1, is also active in G1 phase and controls levels of mitosis regulating proteins.
SCF controls G1/S through G2/M transitions. Two F-box-protein-bound SCF complexes (SCF-Skp2 and SCF-β-TrCP), are most well studied among over 70 F-box proteins identified in human. SCF-Skp2 mainly ubiquitinates and degrades cyclin-dependent-kinase inhibitors (CKIs) such as p27 and p21 as well as G1/S cyclin, CyclinE, in vivo and in vitro . Therefore SCF-Skp2 promotes cell cycle progression and cell growth . On the other hand, SCF- βTrCP promotes proteolysis of Emi1, an APC/C- Cdh1 inhibitor, and Wee1, a Cdk1 inhibitor, in early mitosis via phosphorylation at their degron (DSGXXS amino acid motif. X can be any amino acid) by kinases such as Polo-like kinase 1 (Plk1) and Cdk1-cyclinB. SCF-βTrCP and APC/C control each other to regulate timely cell cycle progression. Lists of substrates of SCF-Skp2 and -βTrCP are still growing.
Auxin stimulates binding of SCF-TIR1 to the AUX/IAA repressor, and its degradation, resulting in the activation of auxin-responsive genes. The TIR1 F-box protein acts as an auxin receptor and directly links auxin perception to degradation of the Aux/IAA proteins. TIR1 (Transport Inhibitor Response 1) is related to AFB (Auxin Signaling F-box).
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
complex catalyzing the 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...
ation of proteins destined for proteasomal
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
degradation. It has important roles in the ubiquitination of proteins involved in the cell cycle as well as having a role in the marking various other cellular proteins for destruction.
SCF contains three core subunits, and a number of less critical components:
- F-box proteinF-box proteinF-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....
- (Such as cdc4CDC4CDC4 may refer to:* Cell division control protein 4* Saint-Quentin Aerodrome...
) Contributes to the specificity of SCF by aggregating to target proteins independently of the complex and then binding to the Skp1 component, thus allowing the protein to be brought into proximity with the functional E2 protein. The F-box is also essential in regulating SCF activity during the course of the cell-cycle. SCF levels are thought to remain constant throughout the cell-cycle. Instead, F-box affinity for protein substrates is regulated through cdk/cyclin mediated phosphorylation of target proteins. - Skp1Skp1Skp1 is a small protein of approximately 160 amino acids. As a core component of the SCF-type E3 ubiquitin ligases that mediate protein degradation by the 26S proteosome, Skp1 plays key roles in cell-cycle progression, transcriptional regulation, signal transduction, and many other cellular...
- Bridging protein, forms part of the horseshoe-shaped complex, along with cullin (cul1). Skp1 is essential in the recognition and binding of the F-box. - CullinCullinCullins are a family of hydrophobic proteins providing a scaffold for ubiquitin ligases . All eukaryotes appear to have cullins. They combine with RING proteins to form Cullin-RING ubiquitin ligases that are highly diverse and play a role in a myriad of cellular processes.Human genome contains...
(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....
) forms the major structural scaffold of the SCF complex, linking the skp1 domain with the Rbx1 domain. - RBX1RBX1RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.-Interactions:RBX1 has been shown to interact with CUL4A, CAND1, CUL1, CUL2, P70-S6 Kinase 1, DCUN1D1, CUL5 and CUL7.-Further reading:...
- Rbx1 contains a small zinc-binding domain called the RING Finger, to which the E2-ubiquitin conjugate binds, allowing the transferral of the ubiquitin to a lysineLysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residue on the target protein.
Progression of eukaryotic cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
is regulated through synthesis-degradation and phosphorylation-dephosphorylation of cell cycle regulating proteins. Two ubiquitin ligases are crucial in cell cycle. The anaphase-promoting complex or cyclosome (APC/C) controls metaphase
Metaphase
Metaphase, from the ancient Greek μετά and φάσις , is a stage of mitosis in the eukaryotic cell cycle in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells...
-anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
transition with its activator Cdc20
CDC20
The cell-division cycle protein 20 is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex , a large 11-13 subunit complex that initiates chromatid separation...
. Its activity is required for sister chromatids
Sister chromatids
Sister chromatids are two identical copies of a chromatid connected by a centromere. Compare sister chromatids to homologous chromosomes, which are the two different copies of the same chromosome that diploid organisms inherit, one from each parent...
separation. APC/C with another activator, Cdh1, is also active in G1 phase and controls levels of mitosis regulating proteins.
SCF controls G1/S through G2/M transitions. Two F-box-protein-bound SCF complexes (SCF-Skp2 and SCF-β-TrCP), are most well studied among over 70 F-box proteins identified in human. SCF-Skp2 mainly ubiquitinates and degrades cyclin-dependent-kinase inhibitors (CKIs) such as p27 and p21 as well as G1/S cyclin, CyclinE, in vivo and in vitro . Therefore SCF-Skp2 promotes cell cycle progression and cell growth . On the other hand, SCF- βTrCP promotes proteolysis of Emi1, an APC/C- Cdh1 inhibitor, and Wee1, a Cdk1 inhibitor, in early mitosis via phosphorylation at their degron (DSGXXS amino acid motif. X can be any amino acid) by kinases such as Polo-like kinase 1 (Plk1) and Cdk1-cyclinB. SCF-βTrCP and APC/C control each other to regulate timely cell cycle progression. Lists of substrates of SCF-Skp2 and -βTrCP are still growing.
Auxin stimulates binding of SCF-TIR1 to the AUX/IAA repressor, and its degradation, resulting in the activation of auxin-responsive genes. The TIR1 F-box protein acts as an auxin receptor and directly links auxin perception to degradation of the Aux/IAA proteins. TIR1 (Transport Inhibitor Response 1) is related to AFB (Auxin Signaling F-box).