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.
Highlights
As with actors on a stage, the timely exit of cellular proteins is as important as their entrance; they must play their part at the appropriate moment and depart on command
We present a brief outline of the function and diversity of the F-box proteins (FBPs) family, describing how they operate within the ubiquitin proteasome system (UPS) system as conventional components of SCFtype E3 ubiquitin ligases
As illustrated by the exemplary case of Fbxo7, we propose that having both ubiquitination functions and noncanonical regulatory roles endows a subset of special FBPs with the potential to act as hubs to link the UPS to other cellular signalling networks
Summary
F-box proteins (FBPs) are substrate-recruiting subunits of Skp1-cullin1-FBP (SCF)-type E3 ubiquitin ligases. A growing body of work has identified non-canonical, SCF-independent roles for about 12% of the human FBPs. 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. We review Fbxo 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 Cdk 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
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