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Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins.

Nelson DE, Randle SJ, Laman H - Open Biol (2013)

Bottom Line: These atypical FBPs affect processes as diverse as transcription, cell cycle regulation, mitochondrial dynamics and intracellular trafficking.We review its function as a cell cycle regulator, via its ability to stabilize p27 protein and Cdk6 complexes, and as a proteasome regulator, owing to its high affinity binding to PI31.We postulate that a few extraordinary FBPs act as platforms that seamlessly segue their canonical and non-canonical functions to integrate different cellular pathways and link their regulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.

ABSTRACT
F-box proteins (FBPs) are substrate-recruiting subunits of Skp1-cullin1-FBP (SCF)-type E3 ubiquitin ligases. To date, 69 FBPs have been identified in humans, but ubiquitinated substrates have only been identified for a few, with the majority of FBPs remaining 'orphans'. In recent years, a growing body of work has identified non-canonical, SCF-independent roles for about 12% of the human FBPs. These atypical FBPs affect processes as diverse as transcription, cell cycle regulation, mitochondrial dynamics and intracellular trafficking. Here, we provide a general review of FBPs, with a particular emphasis on these expanded functions. We review Fbxo7 as an exemplar of this special group as it has well-defined roles in both SCF and non-SCF complexes. We review its function as a cell cycle regulator, via its ability to stabilize p27 protein and Cdk6 complexes, and as a proteasome regulator, owing to its high affinity binding to PI31. We also highlight recent advances in our understanding of Fbxo7 function in Parkinson's disease, where it functions in the regulation of mitophagy with PINK1 and Parkin. We postulate that a few extraordinary FBPs act as platforms that seamlessly segue their canonical and non-canonical functions to integrate different cellular pathways and link their regulation.

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F-box proteins. (a) Schematic of active SCF complexes, which are neddylated (Nedd8 moiety attached to cullin1). FBPs can bind to the SCF holoenzyme alone, with accessory cofactors, or as a homo- or heterodimer allowing for dimeric SCF complex formation. The SCF complex is orientated so the lysine residue (K) in the substrate, usually recruited by FBPs after being PTM, is in close proximity to the ubiquitin moiety on the E2 enzyme. SCF complexes can be inactivated by deneddylation, at which point Cand1 can compete with Skp1/FBP for binding to cullin1, allowing for exchange of SCF subunits. (b) There are three classes of FBP, which are listed, along with examples from each group.
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RSOB130131F1: F-box proteins. (a) Schematic of active SCF complexes, which are neddylated (Nedd8 moiety attached to cullin1). FBPs can bind to the SCF holoenzyme alone, with accessory cofactors, or as a homo- or heterodimer allowing for dimeric SCF complex formation. The SCF complex is orientated so the lysine residue (K) in the substrate, usually recruited by FBPs after being PTM, is in close proximity to the ubiquitin moiety on the E2 enzyme. SCF complexes can be inactivated by deneddylation, at which point Cand1 can compete with Skp1/FBP for binding to cullin1, allowing for exchange of SCF subunits. (b) There are three classes of FBP, which are listed, along with examples from each group.

Mentions: The array of targets regulated by E3 ubiquitin ligases is as broad as the proteome itself. One strategy the cell employs to handle the magnitude of this task is to express a large number of different E3 ligases. Indeed, the human genome encodes over 500 distinct E3s [9], roughly separated across two main families; the homologous to E6-associated protein (E6-AP) C-terminus (HECT) domain and the really interesting new gene (RING) finger domain E3s [3]. Another strategy that goes beyond merely increasing E3 numbers is to employ adaptor proteins that change the substrate specificity of the E3, which may enable a tailoring of substrate engagement with a ligase as per the changing needs of the cell. This strategy is typified by the Skp1-cullin1-F-box protein (SCF)-type E3 ubiquitin ligases, the largest group of multi-subunit E3 ligases within the RING finger domain family [5,10,11]. The F-box protein (FBP) family is fundamental to this flexible substrate-recognition, as they act as interchangeable docking sites for the ligase. The SCF holoenzyme is formed around a central cullin (Cul1) backbone, which provides a rigid scaffold, holding the E2 binding subunit, Rbx1, at a distance of approximately 50 Å from the substrate docking site (figure 1a) [8]. Substrate recruitment is the role of the FBP, and its tethering to cullin is mediated by Skp1.Figure 1.


Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins.

Nelson DE, Randle SJ, Laman H - Open Biol (2013)

F-box proteins. (a) Schematic of active SCF complexes, which are neddylated (Nedd8 moiety attached to cullin1). FBPs can bind to the SCF holoenzyme alone, with accessory cofactors, or as a homo- or heterodimer allowing for dimeric SCF complex formation. The SCF complex is orientated so the lysine residue (K) in the substrate, usually recruited by FBPs after being PTM, is in close proximity to the ubiquitin moiety on the E2 enzyme. SCF complexes can be inactivated by deneddylation, at which point Cand1 can compete with Skp1/FBP for binding to cullin1, allowing for exchange of SCF subunits. (b) There are three classes of FBP, which are listed, along with examples from each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814724&req=5

RSOB130131F1: F-box proteins. (a) Schematic of active SCF complexes, which are neddylated (Nedd8 moiety attached to cullin1). FBPs can bind to the SCF holoenzyme alone, with accessory cofactors, or as a homo- or heterodimer allowing for dimeric SCF complex formation. The SCF complex is orientated so the lysine residue (K) in the substrate, usually recruited by FBPs after being PTM, is in close proximity to the ubiquitin moiety on the E2 enzyme. SCF complexes can be inactivated by deneddylation, at which point Cand1 can compete with Skp1/FBP for binding to cullin1, allowing for exchange of SCF subunits. (b) There are three classes of FBP, which are listed, along with examples from each group.
Mentions: The array of targets regulated by E3 ubiquitin ligases is as broad as the proteome itself. One strategy the cell employs to handle the magnitude of this task is to express a large number of different E3 ligases. Indeed, the human genome encodes over 500 distinct E3s [9], roughly separated across two main families; the homologous to E6-associated protein (E6-AP) C-terminus (HECT) domain and the really interesting new gene (RING) finger domain E3s [3]. Another strategy that goes beyond merely increasing E3 numbers is to employ adaptor proteins that change the substrate specificity of the E3, which may enable a tailoring of substrate engagement with a ligase as per the changing needs of the cell. This strategy is typified by the Skp1-cullin1-F-box protein (SCF)-type E3 ubiquitin ligases, the largest group of multi-subunit E3 ligases within the RING finger domain family [5,10,11]. The F-box protein (FBP) family is fundamental to this flexible substrate-recognition, as they act as interchangeable docking sites for the ligase. The SCF holoenzyme is formed around a central cullin (Cul1) backbone, which provides a rigid scaffold, holding the E2 binding subunit, Rbx1, at a distance of approximately 50 Å from the substrate docking site (figure 1a) [8]. Substrate recruitment is the role of the FBP, and its tethering to cullin is mediated by Skp1.Figure 1.

Bottom Line: These atypical FBPs affect processes as diverse as transcription, cell cycle regulation, mitochondrial dynamics and intracellular trafficking.We review its function as a cell cycle regulator, via its ability to stabilize p27 protein and Cdk6 complexes, and as a proteasome regulator, owing to its high affinity binding to PI31.We postulate that a few extraordinary FBPs act as platforms that seamlessly segue their canonical and non-canonical functions to integrate different cellular pathways and link their regulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.

ABSTRACT
F-box proteins (FBPs) are substrate-recruiting subunits of Skp1-cullin1-FBP (SCF)-type E3 ubiquitin ligases. To date, 69 FBPs have been identified in humans, but ubiquitinated substrates have only been identified for a few, with the majority of FBPs remaining 'orphans'. In recent years, a growing body of work has identified non-canonical, SCF-independent roles for about 12% of the human FBPs. These atypical FBPs affect processes as diverse as transcription, cell cycle regulation, mitochondrial dynamics and intracellular trafficking. Here, we provide a general review of FBPs, with a particular emphasis on these expanded functions. We review Fbxo7 as an exemplar of this special group as it has well-defined roles in both SCF and non-SCF complexes. We review its function as a cell cycle regulator, via its ability to stabilize p27 protein and Cdk6 complexes, and as a proteasome regulator, owing to its high affinity binding to PI31. We also highlight recent advances in our understanding of Fbxo7 function in Parkinson's disease, where it functions in the regulation of mitophagy with PINK1 and Parkin. We postulate that a few extraordinary FBPs act as platforms that seamlessly segue their canonical and non-canonical functions to integrate different cellular pathways and link their regulation.

Show MeSH
Related in: MedlinePlus