SCF complex

Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction. ==Core components== SCF contains a variable F-box protein and three core subunits: F-box protein (FBP) – FBP contributes to the substrate specificity of the SCF complex by first aggregating to target proteins independently of the complex. Each FBP (e.g. Skp2) may recognize several different substrates in a manner that is dependent on post-translational modifications such as phosphorylation or glycosylation. FBP then binds to Skp1 of the SCF complex using an F-box motif, bringing the target protein into proximity with the functional E2 ubiquitin-conjugating enzyme. FBP 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, FBP affinity for protein substrates is regulated through cyclin-CDK-mediated phosphorylation of target proteins. Skp1 – Skp1 is an adaptor protein that is essential for the recognition and binding of F-box proteins. Cullin (CUL1) – Cullin forms the major structural scaffold of the SCF complex and links the skp1 domain to the Rbx1 domain. Different combinations of Cullin and FBPs can generate on the order of a hundred types of E3 ubiquitin ligases that target different substrates. RBX1 – Rbx1 contains a small, zinc-binding Really Interesting New Gene (RING) finger domain, to which the E2 ubiquitin-conjugating enzyme binds. This binding event allows the transferral of ubiquitin from E2 to a lysine residue on the target protein. ==Cell cycle regulation== The eukaryotic cell cycle is regulated through the synthesis, degradation, binding interactions, post-translational modifications of regulatory proteins. Of these regulatory proteins, two ubiquitin ligases are crucial for progression through cell cycle checkpoints. The anaphase-promoting complex (APC) controls the metaphase-anaphase transition, while the SCF complex controls G1/S and G2/M transitions. Specifically, SCF has been shown to regulate centriole splitting from late telophase to the G1/S transition. SCF activity is largely regulated by post-translational modifications. For instance, ubiquitin-mediated autocatalytic degradation of FBPs is a mechanism of decreasing SCF activity. Well-characterized cell cycle substrates of SCF complexes include: cyclin family proteins: Cyclin D, Cyclin E transcriptional regulators: Myc, E2f1, p130 cyclin-dependent kinase inhibitors (CKIs): p27 Kip1 , p21, Wee1 centriole proteins: Cep250, Ninein There are approximately seventy human FBPs, several of which are involved in cell cycle control as a component of SCF complexes. Skp2 is an FBP that binds CKIs such as p27 Kip1 and p21. Skp2 binds p27 Kip1 only when two conditions are met: p27 Kip1 is phosphorylated by E/A/CKD2 and bound to Cks1. As a consequence of binding Skp2, p27 Kip1 is ubiquitinated and targeted for degradation in late G1 and early S. SCF-Skp2 also targets p130 for degradation in a phosphorylation dependent manner. Beta-transducin repeat-containing protein (βTRCP) is an FBP that targets emi1—an APC/C-Cdh1 inhibitor—and wee1 for degradation during early mitosis. βTRCP recognizes these substrates after they are phosphorylated by Polo-like kinase 1 or Cyclin B-CDK1. Fbw7, which is the human homolog of cdc4 in yeast, is an FBP that targets Cyclin E, Myc, Notch and c-Jun for degradation. Fbw7 is stable throughout the cell cycle and is localized to the nucleus due to the presence of a nuclear localization sequence (NLS). SCF-Fbw7 targets Sic1—when at least six out of nine possible sites are phosphorylated—and Swi5 for degradation. Since Sic1 normally prevents premature entry into S-phase by inhibiting Cyclin B-CDK1, targeting Sic1 for degradation promotes S-phase entry. Fbw7 is known to be a haplo-insufficient tumor suppressor gene implicated in several sporadic carcinomas, for which one mutant allele is enough to disturb the wild type phenotype. Fbxo4 is another tumor suppressor FBP that has been implicated in human carcinomas. SCF-fbxo4 plays a role in cell cycle control by targeting cyclin D1 for degradation. Cyclin F is an FBP that is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations that prevent phosphorylation of Cyclin F alter the activity of SCF-Cyclin F, which likely affects downstream processes pertinent to neuron degeneration in ALS and FTD. Normally, Cyclin F targets E2f1 for degradation. ==References== Image:SCF_Morgan.jpg|Morgan, David "Protein Degradation in Cell-Cycle Control", The Cell Cycle; Principles of Control 2007 Image:APC_B-TrcP.jpg|Hartmut C. Vodermaier (2004). "APC/C and SCF: Controlling Each Other and the Cell Cycle", Current Biology, 14 (787)

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