Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitination of proteins involved in the cell cycle and also marks various other cellular proteins for destruction.
SCF contains three core subunits, and a number of less critical components:
- F-box protein (e.g. Cdc4) – 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.
- Skp1 – Skp1 is a bridging protein and forms part of the horseshoe-shaped complex in tandem with cullin (cul1). Skp1 is essential in the recognition and binding of the F-box.
- Cullin (CUL1) – CUL1 forms the major structural scaffold of the SCF complex and links the skp1 domain with the Rbx1 domain.
- RBX1 – 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 lysine residue on the target protein.
SCF and Cell Cycle Regulation
Progression through the cell cycle in eukaryotes is regulated through synthesis/degradation and phosphorylation/dephosphorylation of cell-cycle-regulating proteins. Two ubiquitin ligases are crucial in the cell cycle. The anaphase-promoting complex or cyclosome (APC/C) controls the metaphase–anaphase transition when bound to its substrate-specific activating subunit Cdc20: this complex ubiquitinylates the separase-inhibiting protein securin, paving the way for separase to break cohesin and thus separate the sister chromatids at the centromere. APC/C with another activating subunit, Cdh1, is active in G1 phase and controls levels of the mitosis-regulating B-type cyclins.
SCF controls the transitions between G1/S and G2/M phases. 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 humans. SCF-Skp2 mainly ubiquitinates and degrades cyclin-dependent kinase inhibitors (CKIs) such as p27 and p21 as well as the G1-/S-specific cyclin E, 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 (the amino acid motif DSGXXS, where X can be any amino acid) by kinases such as Polo-like kinase 1 (Plk1) and Cdk1–cyclin B. SCF-βTrCP and APC/C control each other to regulate timely progression through the cell cycle. Lists of substrates of SCF-Skp2 and -βTrCP are still growing.
SCF and Plant Hormone Signaling
In plants, the plant hormone auxin stimulates binding of SCF-TIR1 to the AUX/IAA repressor and then the degradation of the repressor, resulting in the activation of auxin-responsive genes. The TIR1 F-box protein acts as an auxin receptor and directly links reception of auxin to degradation of the Aux/IAA proteins. TIR1 (Transport Inhibitor Response 1) belongs to AFBs (Auxin Signaling F-box proteins).
In plants, the plant hormone Jasmonate allows binding between SCF-COI1 to the JAZ transcription factor. Degradation of the JAZ transcription factor allows for the transcription of the jasmonate responsive genes.
- Morgan, David "Protein Degradation in Cell-Cycle Control", The Cell Cycle; Principles of Control 2007
- David Frescas and Michele Pagano (2008). "Deregulated proteolysis by the F‑box proteins SKP2 and β‑TrCP: tipping the scales of cancer’, NATURE REVIEWS cancer 8 (441).
- Keiichi I. Nakayama and Keiko Nakayama (2005). "Regulation of the cell cycle by SCF-type ubiquitin ligases", Seminars in Cell & Developmental Biology, 16 (323).
- Hartmut C. Vodermaier (2004). "APC/C and SCF: Controlling Each Other and the Cell Cycle", Current Biology, 14 (787)
- Dharmasiri, Nihal; Sunethra Dharmasiri; Mark Estelle (2005). "The F-box protein TIR1 is an auxin receptor". Nature. 435 (7041): 441–445. doi:10.1038/nature03543. ISSN 0028-0836. PMID 15917797.
- Devoto, Alessandra; Nieto-Rostro, Manuela; Xie, Daoxin (2002). "COI1 links jasmonate signalling and fertility to the SCF ubiquitin–ligase complex in Arabidopsis". The Plant Journal: 457–466.