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. 2004 Nov 1;18(21):2573–2580. doi: 10.1101/gad.1255304

Systematic analysis and nomenclature of mammalian F-box proteins

Jianping Jin 1, Timothy Cardozo 2, Ruth C Lovering 3, Stephen J Elledge 4, Michele Pagano 2,5, J Wade Harper 1,6
PMCID: PMC525538  PMID: 15520277

Much of the targeted protein ubiquitylation that occurs in eukaryotes is performed by cullin-based E3 ubiquitin ligases, which form a superfamily of modular E3s. The best understood cullin-based E3 is the SCF ubiquitin ligase (Feldman et al. 1997; Skowyra et al. 1997), which is composed of a modular E3 core containing CUL1 and RBX1 (also called ROC1), and a substrate specificity module composed of SKP1 and a member of the F-box family of proteins (Cardozo and Pagano 2004). The CUL1/RBX1 complex functions as a scaffold to assemble the E2 ubiquitin conjugating enzyme with the substrate specificity module (Zheng et al. 2002). CUL1 interacts with RBX1 through its C terminus and with SKP1 through its N terminus. The interaction of F-box proteins with SKP1 occurs through the F-box motif, an ∼40-amino acid motif first identified in budding yeast Cdc4p and human cyclin F, the latter giving the name to the entire family (Bai et al. 1996). F-box proteins contain additional protein interaction domains that bind ubiquitylation targets. The overall architecture of SCF complexes is conserved in the superfamily of SCF-like ubiquitin ligases that use cullin proteins as a scaffold. All cullins characterized to date (CUL1-5) are known to interact with RBX1 or RBX2 but use distinct specificity modules, which generally display structural and functional similarities with the SKP1/F-box protein module. For example, CUL2 and CUL5 are known to interact with the SKP1-like protein elongin C, which, in turn, interacts with F-box protein-like specificity factors called BC/SOCS-box proteins (Deshaies 1999; Guardavaccaro and Pagano 2003). In addition, CUL3 interacts with the BTB/POZ family of proteins, which appear to merge the functions of SKP1 and the F-box protein into a single polypeptide (Furukawa et al. 2003; Geyer et al. 2003; Pintard et al. 2003; Xu et al. 2003), with the BTB domain displaying structural relationships with SKP1 (Schulman et al. 2000; Xu et al. 2003). Cul4 forms a complex wherein DDB1/DDB2 and CSA proteins appear to function as substrate specificity modules (Groisman et al. 2003). Thus, the current expectation is that all cullin-containing ligases will share the modular nature of the original SCF family of ligases.

A major strategy employed by the SCF is the use of extended protein families as specificity factors. In 1999, we reported the identification of 47 F-box proteins in mammals (Cenciarelli et al. 1999; Winston et al. 1999). These proteins fell into three major classes, depending on the types of substrate interaction domains identified in addition to the F-box motif. The two largest classes of interaction domains are WD40 repeats (Smith et al. 1999) and leucine-rich repeats (LRRs) (Kobe and Kajava 2001). A third generic class of F-box proteins contained various other types of protein interaction domains or no recognizable domains. These classes of F-box proteins were designated FBWs, FBLs, and FBXs, respectively, followed by a numerical identifier (Cenciarelli et al. 1999; Winston et al. 1999). Paralogous genes in the same species used the same number followed by a letter (a, b,...) representing the individual genes in the paralogous group. The Human Genome Organization (HUGO) Gene Nomenclature Committee adopted a related four-letter gene nomenclature: FBXW, FBXL, and FBXO, respectively, where “O” in FBXO refers to “other” domains. Since this initial work, subsequent efforts, particularly cDNA and genomic sequencing projects, have facilitated the further identification of F-box protein-coding genes. However, the inconsistent use of nomenclature standards has greatly limited the utility of the sequence database. This inconsistency is due in part to the rapid pace of research in this area that has precluded coordination of gene names. A survey of F-box proteins in GenBank revealed several issues: (1) several different F-box protein coding genes have been given the same gene name; (2) multiple individual F-box genes have been given several different names; (3) the nomenclature used for clearly orthologous mouse and human genes is inconsistent; (4) several genes present in GenBank encode F-box proteins but are not annotated as such; (5) mRNA sequence revisions and refinement of algorithms for detection of F-box motifs have led to the removal of some genes from the F-box category; and (6) improvements in structural domain identification suggest that genes previously designated in the FBXO subclass may be more appropriately placed in the FBXL or FBXW subclasses. The need for clear communication in this field necessitates a unified nomenclature for F-box proteins.

To develop a comprehensive nomenclature for mammalian F-box proteins, we have systematically analyzed F-box proteins in the human and mouse genomes and have organized these genes in a manner that largely conforms to previous nomenclature standards, as explained below. This nomenclature has now been adopted and implemented by the HUGO Gene Nomenclature Committee. Several factors were considered in devising the most appropriate nomenclature for the future. First, genes whose symbols were approved by the nomenclature committee prior to the discovery of these genes as F-box proteins will remain as the approved symbol. Second, the previous nomenclature used letters (a, b,...) to indicate what appeared to be paralogous genes (e.g., FBXL3a and FBXL3b). However, because it is now appreciated that many F-box proteins exist as multiple splicing variants, the use of such a designation scheme has been avoided, necessitating the complete renaming of a small number of F-box proteins. Finally, mouse and human orthologs have been given the same symbols to facilitate comparative studies in the future. A detailed description of how the nomenclature changes have affected individual F-box genes is provided in the Supplemental Material.

Our analysis led to the identification of 68 human and 74 mouse genes encoding recognizable F-box motifs, as detected by Hidden Markov Models (Table 1; Fig. 1) (Bateman et al. 2004; Letunic et al. 2004). A phylogenetic representation of human F-box motifs is shown in Figure 2. The phylogeny of F-box domain sequences only, which gives the cleanest available view of the evolutionary signature of the family, shows two major groups of F-box proteins (an evolutionary divergence). Different protein interaction domains are scattered throughout the two groups indicating that similar domain swapping mechanisms acted on both, but ruling out that all FBXW subfamily members diverged from a single FBXW ancestor, for example.

Table 1.

Mammalian F-box proteins

F-box protein Revised HUGO gene symbol Aliases Human Entrez gene ID Human location Mouse accession % identity Mouse location Fly ortholog Worm ortholog Other domains (c)
FBXW1 (β-TRCP1) BTRC Fwd1, FBXW1A 8945 10q24.32 NM 009771 99 19C3 slmb (CG3412) lin-23 (K10B2.1)
FBXW2 FBXW2 Fwd2, MD6 26190 9q34 NM 013890 98 2B
FBXW4 (Dactylin) SHFM3 FBXW4 6468 10q24 NM 13907 92 19C3
FBXW5 FBXW5 54461 9q34.3 NM 013908 88 2A3 CG9144
FBXW7 FBXW7 FBXW6, Cdc4, Sel-10, Fbx30 55294 4q31.3 NM 080428 97 3E3.3 ago (CG15010) sel-10 (F55B12.3) transmembrane domain in β-isoform
FBXW8 FBXW8 Fbx29, FBXO29, Fbw6 26259 12q24.23 NM_172721 71 5F
FBXW9 FBXW9 84261 19p13.2 BC043658.1 64 9 T01E8.4
FBXW10 FBXW10 C17orf1A 10517 17p12 XM 126264.2 62 11B2
FBXW11 (β-TRCP2) FBXW11 Hos, FBXW1B, BTRC2, Fbx1b 23291 5q35.1 NM 134015 99 11A4 slmb (CG3412) lin-23 (K10B2.1)
FBXW12 FBXW12 FBXO35 285231 3p21.31
Fbxw13 Fbxw13 NM 177598 9F2
Fbxw14 Fbxw14 Fbx12, Fbxo12 NM 015793 9F2
Fbxw15 Fbxw15 AK087669 9F2
Fbxw16 Fbxw16 AK078661 9F2
Fbxw17 Fbxw17 AAH40428 13A5
Fbxw18 Fbxw18 XM 356193 9F2
Fbwx19 Fbxw19 AK087808 9F2
FBXL1 (SKP2) SKP2 FBXL1 6502 5p13 NM 013787.1 86 15A2 CG9772
FBXL2 FBXL2 Fbl3 25827 3p22.3 NM 178624.2 95 9F3 CG9003 C02F5.7
FBXL3 FBXL3 Fbl3a, FBLX3A 26224 13q22 AF 176521.1 93 14E2.3
FBXL4 FBXL4 Fbl5 26235 6q16.1 NM 172988.1 93 4A3 CG1839
FBXL5 FBXL5 Fbl4, Fir4 26234 4p15.33 AK085100 88 5B3
FBXL6 FBXL6 26233 8q24.3 NM 013909 75 15
FBXL7 FBXL7 Fbl6 23194 5p15.1 AK129227.1 93 15B1 CG4221
FBXL8 FBXL8 55336 16q22.1 NM 015821 61 8D3
FBXL10 FBXL10 84678 12q24.31 AK129479.1 84 4A5 DG11033 PHD, ZF, Jmjc
FBXL11 FBXL11 Lilina, Fbl7 22992 11q13.1 BC057051 90 19A CG11033 PHD, ZF, Jmjc
FBXL12 FBXL12 54850 19p13.2 AF176525.1 93 9A3
FBXL13 FBXL13 222235 7q22.1 NM 177076.2 63 5A3
FBXL14 FBXL14 144699 12p13.33 AK084506.1 100 6F1 ppa (CG9952)
FBXL15 FBXL15 FBXO37 79176 10q24.32 NM 133694.1 87 19C3 CG8873
FBXL16 FBXL16 C16orf22 146330 16p13.3 XM 128530.4 81 17A3.3 CG32085
FBXL17 FBXL17 Fbx13, FBXO13 64839 5q21.3 XM 128716.2 93 17E1.1
FBXL18 FBXL18 80028 7p22.2 Bl853840 89 5G2
FBXL19 FBXL19 54620 16p11.2 NM 172748.2 95 7F3 PHD, ZF
FBXL20 FBXL20 Fbl2 84961 17q21.2 XM 126674.3 99 11D CG9003 CO2F5.7
FBXL21 FBXL21 FBXL3B, Fbl3B 26223 5q31 AK035290 81 13B1
FBXL22 FBXL22 400380 15q22.1 NM 175206 80 9C
FBXO1 (Cyclin F) CCNF FBX1, FBXO1 899 16p13.3 NM 007634.2 75 17A3.3 cyclin box
FBXO2 FBXO2 Nfb42, Fbs1, Fbg1, Ocp1 26232 1p35.21 BC027053.1 87 4E2.0 FBA
FBXO3 FBXO3 FBA 26273 11p13 AK004544.2 92 2E2.0 ApaG-like domain (SCOP)
FBXO4 FBXO4 26272 5p12 NM 134099.1 83 15A1
FBXO5 (EMI1) FBXO5 FBXO31 26271 6q25 BC053434.1 70 10A1 Rca1 (CG10800) IBR domain
FBXO6 FBXO6 Fbs2, Fbg2, Fbx6b 26270 1p36.23 NM 015797 75 4E2.0 C14B1.3 FBA domain
FBXO7 FBXO7 Fbx 25793 22q12-q13 NM 153195.1 70 10C1 UBL-domain (SCOP)
FBXO8 FBXO8 Fbs 26269 4q34.1 NM 015791.2 90 8B1.3 Sec7
FBXO9 FBXO9 Ny-ren-57 26268 6p12.3-p11.2 AK077607.1 89 9E1.0 CG5961 TPR, HNHc (SCOP)
FBXO10 FBXO10 26267 9p13.1 XM_194139.2 84 4B1 CG9461 K04A8.6 CASH
FBXO11 FBXO11 80204 2p21 XM_110248.4 98 17E5.0 CG9461 K04A8.6 CASH
FBXO15 FBXO15 201456 18q22.3 AF176530 60 18E4.0
FBXO16 FBXO16 157574 8p21.1 NM 015795.1 81 14D1
FBXO17 FBXO17 Fbg4, FBXO26 115290 19q13.2 AF176532/NM 015796 80 7A3 FBA
FBXO18 FBXO18 Fbh1 84893 10p15.1 NM 015792 87 2A1 Helicase
FBXO20 LMO7 FBXO20 4008 13q21.33 AK129231 68 14E2.2 CH, PDZ, Lim
FBXO21 FBXO21 23014 12q24.23 AB093270 91 5F
FBXO22 FBXO22 26263 15q23 NP 028049 96 9B
FBXO24 FBXO24 26261 7q22 XM 132440 84 5G2 RCC1-fold (SCOP)
FBXO25 FBXO25 26260 8p23.3 NM 025785 84 8A1.1 CG11658 DY3.6
FBXO27 FBXO27 Fbg5 126433 19q13.2 AK053292 79 7A3 FBA
FBXO28 FBXO28 23219 1q42.12 NM 175127 89 1H5 CG3428
FBXO30 FBXO30 84085 6q24 XM 125493 87 10A1
FBXO31 FBXO31 Fbx14, FBXO14 79791 16 AU066822/NM 133765.2 95 8.00E+01
FBXO32 FBXO32 Mafbx, Atrogin-1 114907 8q24.13 NM_026346 96 15D1 CG11658 DY3.6
FBXO33 FBXO33 254170 14q13.3 XM_127032 90 12C1 CG4911 RNI-like (SCOP)
FBXO34 FBXO34 55030 14q22.2 NM 030236.1 71 14B
FBXO36 FBXO36 130888 2q37.1 NM 025386 78 1C5
FBXO38 FBXO38 MOKA 81545 5q33.1 AK 031347 86 18E2.0 RNI-like (SCOP)
FBXO39 FBXO39 162517 17p13.2 XM 282966 78 11B4 CG2010 RNI-like (SCOP)
FBXO40 FBXO40 51725 3q21.1 XM 156082 80 16A1 TDL (SCOP)
FBXO41 FBXO41 150726 2p13.2 AK129466 80 6C3
FBXO42 FBXO42 54455 1p36.23-p36.11 AK028867 89 4D3 CG6758 Kelch repeats
FBXO43 FBXO43 286151 8q22.3 NM_175281 70 15B3.1 Rca1 (CG10800) IBR domain
FBXO44 FBXO44 Fbx30, FBG3, FBXO6a 93611 1p36.21 NM 173401 90 4E2.0 C14B1.3 FBA domain
FBXO45 FBXO45 20093 3q29 BC026799 99 16A1 SPRY
FBXO46 FBXO46 FBXO34L 23403 9q13.3 NM 175530 80 7A2
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Figure 1.

Figure 1.

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Domain structures of mammalian F-box proteins. Domains identified by the Hidden Markov Model algorithms of SMART or PFam include F-box motif (F), WD40 repeat (WD), leucine-rich repeat (L), transmembrane domain (T), F-box-associated domain (FBA), between-ring domain (IBR), domain in carbohydrate binding proteins and sugar hydrolases (CASH), kelch repeat (K), calponin homology domain (CH), domain found in cupin metalloenzyme family (Jmjc), domain present in PSD-95, Dlg, and ZO-1 (PDZ), zinc-binding domain found in Lin-11, Isl-1, and Mec-3 (Lim), HNH nuclease family (HNHc), novel eukaryotic zinc-binding domain (CHORD), and tetratrico peptide repeat (TPR). The following domains were found via the Structural Classification of Proteins (SCOP) database, which can be used to predict protein sequences that can adopt known protein folds: ApaG-like, which is structurally similar to bacterial ApaG; Apolipophorin, the apolipophorin-III-like fold; Ubl, the ubiquitin-like fold; TDL, which is Traf-domain like; RNI-like, which may form structure similar to that of leucine-rich repeats in placental RNase inhibitor; and RCC1, which is a possible regulator of chromatin condensation-1 fold.

Figure 2.

Figure 2.

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Phylogenetic tree depiction of interrelationships between human F-box proteins. The tree is generated from the pairwise ZEGA distances (Abagyan and Batalov 1997) within the set of amino acid sequences comprising the F-box domain only by the neighbor-joining method (Saitou and Nei 1987) as adapted in ICM software (Molsoft LLC; http://www.molsoft.com).

Clear mouse orthologs were identified for all human F-box proteins except FBXW12, with the majority of mouse genes displaying >80% identity with their human counterparts (Table 1). In the mouse, FBXW12-related sequences have been dramatically expanded to seven genes (one at chromosome 13A5 [Fbxw17] and a cluster of six genes at chromosome 9F2 [Fbxw13, Fbxw14, Fbxw15, Fbxw16, Fbxw18, Fbxw19]). Each of these seven mouse genes is equally related to FBXW12, and, therefore, we are unable to unambiguously designate a mouse ortholog of human FBXW12. The mechanism and significance of expansion of this subclass of F-box proteins in the mouse are unknown. Three human proteins with F-box like motifs—Tome-1 (CDCA3), TBL1, and TBLR1 (TBL1XR1)—were not included because the presumptive F-box sequence did not reach the threshold sufficient for this classification.

A combination of BLAST analyses and phylogenetic tree construction using putative substrate interaction domains together with the F-box motif revealed possible orthologs of mammalian F-box proteins in Drosophila melanogaster and Caenorhabditis elegans (Table 1; Fig. 3). The inclusion of substrate interaction domains allows confirmation of some relationships with the mammalian proteins (e.g., FBXL12 with SKP2), but also demonstrates, in comparison to the F-box domain only tree, that the phylogenetic spread of each subgroup is as wide as that of the whole family. Interestingly, the D. melanogaster genome contains several possible orthologs of the human FBXL series that are not found in C. elegans (Table 1; Fig. 3). The fact that C. elegans has more than 300 F-box proteins but that only a few display relationships with mammalian genes indicates significant diversification of the F-box proteins in this organism. This expansion is species-specific because the Caenorhabditis briggsae genome is predicted to encode a similar number of F-box proteins as found in human and mouse genomes (Stein et al. 2003). Six genes encoding F-box proteins appear to be conserved in C. elegans, D. melanogaster, and mammals: BTRC (FBXW1), FBXW7, FBXL2, FBXO10, FBXO25, and FBXO45 (Table 1; Fig. 3). Interestingly, in mammals four of these six genes have a paralog: FBXW1 (BTRC, β-TRCP1) for FBXW11 (β-TRCP2), FBXL20 for FBXL2, FBXL11 for FBXL10, and FBXO32 for FBXO25, respectively. The FBA-containing subclass of FBXO proteins are contained in the C. elegans genome but are absent in D. melanogaster (Table 1; Fig. 3). Thus, it is possible that much of the core SCF signaling common to metazoans is performed by a relatively small number of highly conserved F-box proteins. To date, conserved degradation pathways have been found for targets of mammalian FBXW7 and β-TRCP1/2 in both C. elegans and Drosophila. c-MYC and cyclin E are targeted by ago/FBXW7 in both Drosophila and mammals (Koepp et al. 2001; Moberg et al. 2001, 2004; Strohmaier et al. 2001; Tetzlaff et al. 2004; Welcker et al. 2004), and Notch is targeted by sel-10/FBXW7 in both mammals and C. elegans (Hubbard et al. 1997; Wu et al. 2001; Tetzlaff et al. 2004; Tsunematsu et al. 2004). Similarly, β-TRCP1/2/slmb has been linked to the β-catenin, IκB, and cell cycle pathways in both Drosophila and mammals (for review, see Maniatis 1999; Guardavaccaro and Pagano 2003).

Figure 3.

Figure 3.

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Phylogenetic trees for FBXW, FBXL, and FBA-domain-containing subfamilies of F-box proteins, along with orthologous sequences from D. melanogaster and C. elegans. Only the contiguous portions of the sequence corresponding to the F-box domain followed by the indicated protein interaction domain were included and aligned.

Despite the large number of mammalian F-box proteins, in addition to β-TRCP1/2 and FBW7, only one other mammalian F-box protein has been matched to its downstream substrates, namely, SKP2 (Ang and Harper 2004; Cardozo and Pagano 2004). Interestingly, SKP2 is the product of a proto-oncogene, FBW7 is a tumor suppressor (Pagano and Benmaamar 2003; Yamasaki and Pagano 2004), and overexpression of β-TRCP1 can contribute to transformation at least in some epithelial tissues (Kudo et al. 2004). Finally, EMI1/FBXO5, an inhibitor of the mitotic ubiquitin ligase APC/C, is overexpressed in tumor cell lines and certain breast tumors (Hsu et al. 2002; van 't Veer et al. 2002). Other F-box proteins appear to play a role in different diseases. For example, Dactylin/FBW4 is encoded by SHFM3, the split hand-foot malformation syndrome gene 3 (Basel et al. 2003). FBXO3 expression is increased in proliferating synovium of patients with rheumatoid arthritis (Masuda et al. 2002). FBXO32 is up-regulated during muscle atrophy (Bodine et al. 2001; Gomes et al. 2001). Thus, F-box proteins are attractive candidates for drug discovery because they play crucial roles in many important signaling pathways.

Validated protein structure prediction tools revealed inappropriately classified F-box proteins as well the association of new functional or structural domains with the F-box motif (Fig. 1). For example, certain F-box proteins previously placed in the FBXO class (e.g., FBXO13) were found to have LRRs and were reclassified accordingly (Table 1; also see Supplemental Material). FBXO14 was found to have WD40 repeats and was reclassified as FBXW12 (Table 1). Three FBXO members (FBXO33, FBXO38, and FBXO39) may display structural similarity to RNase inhibitor, the prototypical LRR, but these sequences do not reach the threshold required to be fingered as authentic LRRs based on sequence information alone (Fig. 1). Additional protein folds new to the mammalian FBX class include ubiquitin-like folds (FBXO7), TPR-like domain (FBXO9), RCC1 (FBXO24), and Kelch repeats (FBXO42). In addition to the five FBA-containing F-box proteins that bind glycosylated proteins (Cardozo and Pagano 2004), two additional proteins (FBXO10 and FBXO11) contain the CASH domain frequently found in carbohydrate-binding proteins and hydrolases (Fig. 1). Both D. melanogaster and C. elegans contain possible orthologs of FBXO10 and/or FBXO11 (Table 1). Finally, F-box proteins containing a SPRY domain (FBXO45 in mammals) are found in all metazoans. The SPRY domain is of unknown function but is frequently present in ryanodine receptors. Recent studies have linked the C. elegans SPRY domain F-box protein (C26E6.5) with presynaptic differentiation (Liao et al. 2004).

The use of this systematic nomenclature should facilitate comparative genomics and drug discovery approaches, as well as the communication of experiments designed to elaborate the functional properties of F-box proteins.

Acknowledgments

This work was supported by NIH grant AG11085 (to J.W.H. and S.J.E), and by the Department of Defense (DAMD17-01-1-0135) to J.W.H., and by NIH grants CA76584 and GM57587 to M.P. J.J. was supported by postdoctoral fellowship DAMD17-02-1-0284. S.J.E. is an investigator of the Howard Hughes Medical Institute.

Supplemental material is available at http://www.genesdev.org.

Corresponding authors.

Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1255304.

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