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Review
. 2013 Oct 9;3(10):130131.
doi: 10.1098/rsob.130131.

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

David E Nelson  1 , Suzanne J Randle, Heike Laman
Affiliations
Review

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

David E Nelson et al. Open Biol. .

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.

Keywords: E3 ligase; F-box protein; Fbxo7/PARK15; Parkinson's disease; mitophagy; ubiquitin.

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Figures

Figure 1.
Figure 1.
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.
Figure 2.
Figure 2.
Common ubiquitin linkages and their consequences. (a) Polyubiquitin chains linked via lysine 48 (K48) to the preceding ubiquitin molecule usually target proteins for degradation via the 26S proteasome. Poly-K48 chains can also result in proteasome-mediated protein cleavage such as in the case of the NF-κB subunits, p100 and p105, being processed into p52 and p50, respectively. (b) Polyubiquitination via lysine 63 (K63) is also common. This type of ubiquitination usually acts as a scaffold for UBPs that recruit other protein complexes, and also mediates alternate outcomes such as changes to cell signalling (e.g. ubiquitinated RIP can recruit NF-κB signalling pathway components), activation of the endosomal pathway (e.g. resulting in internalization of membrane proteins such as receptor tyrosine kinases) and activation of the autophagic/lysosomal pathway (e.g. resulting in degradation of target proteins and organelles independently of the proteasome). (c) Monoubiquitination, or multi-monoubiquitination, can result in changes to substrate function, localization or protein binding.
Figure 3.
Figure 3.
Human Fbxo7 gene and protein structure. (a) FBXO7 gene organization. Orange and red boxes are untranslated and translated portions of exons, respectively, with exon numbers, as indicated. (b) Protein coding Fbxo7 mRNA transcripts, with Ensembl accession numbers and protein size. (c) Fbxo7 isoform 1 protein structure. Protein binding partners are listed below the domains with which they interact. Pathogenic mutations associated with PD are in red, and SNPs associated with red blood cell parameters in black. MTS, mitochondrial targeting signal; Ubl, ubiquitin-like domain; FP, Fbxo7/PI31 interacting domain; R(Ar)DP motif, where Ar is an aromatic amino acid. (d) Fbxo7 functions described for each domain relative to the protein schematic above. They are subdivided into canonical (SCF ligase) and non-canonical functions (mitophagy, cell cycle regulation and proteasome regulation). See text for details.
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