Homo sapiens

    The A20 family represents the zinc finger domain found in A20 (1). A20 is an inhibitor of cell death that inhibits NF-kappaB activation via the tumour necrosis factor receptor associated factor pathway (2). The zinc finger domains appear to mediate self-association in A20. These fingers also mediate IL-1-induced NF-kappa B activation.

1. http://pfam.xfam.org/family/PF01754

2. Ananda S. Prasad (2007). Zinc: mechanisms of host defense. The Journal of Nutrition., 137(5):1345-1349. PMID:17449604

    The DCUN1 domain is an ~190-residue module of unknown function which is found in the eukaryotic defective in cullin neddylation (DCN) protein family. The eukaryotic defective in cullin neddylation (DCN) protein family, may contribute to neddylation of cullin components of SCF-type E3 ubiquitin ligase complexes.

    The HECT ligases are a major group of E3 enzymes which contain the HECT (Homologous to the E6-AP Carboxyl Terminus) domain of ~350 AA at the C-terminus (1). HECT domain is a bifunctional, which binds the E2 enzyme through its N-terminal region while forms the thioester complexes with ubiquitin though the C-terminal cysteine (2). The ubiquitination is catalyzed by directly transferring the ubiquitin to the targeted substrates, which is binded with the N-terminal domain of the HECT ligases. Although the C-terminal cysteines and the HECT domains are conserved in the HECT ligases, the N-terminal domains of the HECT ligases are various, which determine its diversity of the substrate specificity. Furthermore, based on various N-terminal domain, the HECT ligases could be divided into 3 groups of Nedd4, HERC and others. The HECT ligases are involved in various cellular and physiological processes such as mitochondrial inheritance, chromatin remodeling, regulation of transcription, tumorigenesis (2).

1. http://pfam.sanger.ac.uk/family/PF01388

2. Rotin, D. and S. Kumar (2009). Physiological functions of the HECT family of ubiquitin ligases. Nat. Rev. Mol. Cell Biol., 10(6): 398-409. PMID: 19436320

    In the N-end rule pathway, the N-degrons are recognized by N-recognins, a type of E3 ligases. Since there are various N-degrons including UBR-box, N-domain and the others, different protein domains are employed by organisms to recognize (1). The N-domain N-degron (bulky hydrophobic residues; Phe, Leu, Trp, Ile and Tyr) is recognized by a ~80-residue N-domain, which shows sequential, structural and functional similarities with the 106-residue Escherichia coli ClpS, a bacterial N-recognin (2). N-domains are usually found in the downstream from the UBR-boxes. Here we defined the N-domain family as the N- recognins contain the N-domain.

1. Sriram, S.M., Kim, B.Y. and Kwon, Y.T. (2011). The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat. Rev. Mol. Cell Biol., 12, 735-747. PMID: 22016057

2. Tasaki, T., Zakrzewska, A., Dudgeon, D.D., Jiang, Y., Lazo, J.S. and Kwon, Y.T. (2009). The substrate recognition domains of the N-end rule pathway. J. Biol. Chem., 284, 1884-1895. PMID: 19008229

    In the N-end rule pathway, the N-degrons are recognized by N-recognins, a type of E3 ligases. Since there are various N-degrons including UBR-box, N-domain and the others, different protein domains are employed by organisms to recognize (1). The UBR-box N-degron (positively charged residues: Arg, Lys and His) is recognized by UBR-box (ubiquitin-recognin box), a ~70-residue zinc finger-like motif with two alpha-helices, beta-strands and two long ordered loops (2). In the UBR-box protein, the two zinc fingers bind with three zinc ions, which form the N-degron - binding site. Here we defined the UBR-box family as the N-recognins contain the UBR-box domain.

1. Sriram, S.M., Kim, B.Y. and Kwon, Y.T. (2011). The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat. Rev. Mol. Cell. Biol., 12, 735-747. PMID: 22016057

2. Matta-Camacho, E., Kozlov, G., Li, F.F. and Gehring, K. (2010). Structural basis of substrate recognition and specificity in the N-end rule pathway. Nat. Struct. Mol. Biol., 17, 1182-1187. PMID: 20835242

    E3 activity/Other/Other family is a unconventional single protein E3 family that consists of miscellaneous nonclassical domain-containing proteins, such as CREBBP, E4F1, ZFP91, UCHL1, EP300, CBX4, RANBP2,FUS, STC1, HDAC4, KAT2B, MAP3K1, PDLIM2, KDM2B and so on.

    The RBR family of E3 ligases has a distinctive organisation of RING fingers called 'RING-betweenRING-RING' (RBR), characterised by two RING fingers with a cysteine-rich region called the 'in-between-RING' domain that separates them (1, 2, 3). The domains in the RBR E3 ligases have been further named as RING1-BRcat-Rcat according to their structure and function: the C-terminal Rcat (required-for-catalysis) domain is essential for catalytic activity, whereas the central BRcat (benign-catalytic) domain adopts the same fold as the Rcat, but lacks a catalytic cysteine residue and ubiquitination activity (4). These ligases have a unique mechanism of elongating ubiquitin chains that distinguishes them from other E3 ligases.

1. http://www.ebi.ac.uk/interpro/entry/IPR031127

2. Marín et al., 2004. Parkin and relatives: the RBR family of ubiquitin ligases. Physiol Genomics., 17(3):253-63. PMID: 15152079

3. Marín, 2009. RBR ubiquitin ligases: Diversification and streamlining in animal lineages. J Mol Evol., 69(1):54-64. PMID: 19526189

4. Spratt et al., 2014. RBR E3 ubiquitin ligases: new structures, new insights, new questions. Biochem J., 458(3):421-37. PMID: 24576094

    The plant homeodomain (PHD) zinc finger domain has a C4HC3-type motif, and is widely distributed in eukaryotes, being found in many chromatin regulatory factors (1).PHD is thought to be involved in chromatin-mediated transcriptional regulation (2). The PHD finger motif is reminiscent of, but distinct from the C3HC4 type RING finger.

1. http://pfam.xfam.org/family/PF00628

2. Rein Aasland, Toby J. Gibson, A.Francis Stewart (1995). The PHD finger: Implications for chromatin-mediated transcriptional regulation. Trends in Biochemical Sciences., 20(2):56-59. PMID:77015622

    RING, which is the abbreviation of "Really Interesting New Gene", represents a zinc finger type structural domain with a C3HC4 amino acid motif which binds two zinc cations (1). It is observed that the cysteine and histidine residues are conserved and help maintain the structure. During the ubiquitination catalyzed by RING E3s, the ubiquitin is directly transferred from E2 to the substrate. Although the RING ligases might be single chains or complexes, the RING domains present the E3 ligase activity by binding E2s and activate E2s to discharge its ubiquitin cargo. Furthermore, RING domain proteins usually function as oligomers. Since the organization of RING E3 ligases, RING domain proteins are involved in a variety of biological functions (2).

1. http://pfam.xfam.org/family/PF00097

2. Deshaies, R.J. and Joazeiro, C.A. (2009). RING domain E3 ubiquitin ligases. Annu. Rev. Biochem., 78, 399-434. PMID: 19489725

    The U-box is a protein domain with about 70 amino acids. Although the U-box domain is similar with the RING domain, the zinc-binding sites in the RING domain are replaced by conserved charged and polar residues to maintain structure and activity (1). Previously, the U-box protein was considered as a ubiquitin chain assembly factor to catalyze the formation of a ubiquitin chain on ubiquitinated substrates, while recent studies showed that it could mediate polyubiquitylation in the absence of a HECT type or RING-finger type E3. Although the understanding of the detailed mechanisms and functions of the U-box proteins are still limited, it is proposed that they are involved in various biological processes such as the cellular stress response to the intracellular accumulation of abnormal proteins (2).

1. http://www.ebi.ac.uk/interpro/entry/IPR003613

2. Hatakeyama, S. and K. I. Nakayama (2003) U-box proteins as a new family of ubiquitin ligases. Biochem. Biophys. Res. Commun., 302(4): 635-45. PMID: 12646216

    APC/C is a large multisubunit complex that consists of at least 10 subunits, APC1, APC2, APC3/CDC27, APC4, APC5, APC6/CDC16, APC8/CDC23, APC10/DOC1, APC11 and APC13, without containing proteins of CDC20 family here. In human, APC/C and CDC20 can form a 13 subunits containing ubiquitin ligase complex responsible for mediating defined cell cycle transitions. For instance, this unusual complex ubiquitin ligase can ubiquitinate and degrade cell-cycle-related proteins like cyclins and securing duiring mitosis and meiosis. Phosphorylation and inhibitors can regulate the APC/C and alter its substrate specificity at different phases of the cell cycle. Such strict control assures accurately timed degradation of critical cell-cycle regulators (1,2).

1. Schreiber, A., Stengel, F., Zhang, Z., Enchev, R.I., Kong, E.H., Morris, E.P., Robinson, C.V., da Fonseca, P.C. and Barford, D. (2011). Structural basis for the subunit assembly of the anaphase-promoting complex. Nature, 470, 227-232. PMID: 21307936

2. Acquaviva, C and Pines, J. (2006). The anaphase-promoting complex/cyclosome: APC/C. J Cell Sci, 119, 2401-2404. PMID: 16763193

    CDC20 represents a family of substrate-specific activators of APC-dependent ubiquitination, which can promote the degradation of the APC substrate (1). Members of CDC20 family share the C-terminal WD40 domain that recognize and bind substrate (2). In human, there are two members, CDC20 and FZR1, while in yeast there exist three, CDC20, CDH1 and AMA1.

1. Visintin, R., Prinz, S. and Amon, A. (1997). CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis. Science, 278, 460-463. PMID: 9334304

2. Kimata, Y., Baxter, J.E., Fry, A.M. and Yamano, H. (2008). A role for the Fizzy/Cdc20 family of proteins in activation of the APC/C distinct from substrate recruitment. Mol. Cell, 32, 576-583. PMID: 19026787

    BTB (also known as POZ) was first identified as a conserved motif presented in the Drosophila melanogaster Bric-a-Brac, Tramtrack, Broad complex transcription regulators (1). BTB, Cul3 and RBX1 form a Cul3-based ligase (BCR), which targets substrates for ubiquitin-dependent degradation by the 26S proteasome. As a substrate recognition subunit of Cul3-based ligase, the member of BTB family can bridge the Cul3 to the substrate in a single polypeptide (2,3). Recently, it was observed that a 3-box is responsible for the Cul3-interacting in a variety of BTB proteins including almost all of BTB-Kelch and MATH-BTB proteins (4). Here we defined the BTB_3-box family as the proteins contain both BTB domain and 3-box domain. BTB-containing proteins are highly conserved and participate in diverse biological processes, including transcriptional regulation, ion channel assembly and gating, cytoskeleton dynamics, and targeting proteins for ubiquitination (1).

1. Stogios, P.J., Downs, G.S., Jauhal, J.J., Nandra, S.K. and Prive, G.G. (2005). Sequence and structural analysis of BTB domain proteins. Genome Biol., 6, R82. PMID: 16207353

2. Xu, L., Wei, Y., Reboul, J., Vaglio, P., Shin, T.H., Vidal, M., Elledge, S.J. and Harper, J.W. (2003). BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature, 425, 316-321. PMID: 13679922

3. Pintard, L., Willems, A. and Peter, M. (2004). Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family. EMBO J., 23, 1681-1687. PMID: 15071497

4. Zhuang, M., Calabrese, M.F., Liu, J., Waddell, M.B., Nourse, A., Hammel, M., Miller, D.J., Walden, H., Duda, D.M., Seyedin, S.N., Hoggard, T., Harper, J. W., White, K. P. and Schulman, B. A.. (2009). Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol. Cell, 36(1): 39-50. PMID: 19818708

    BTB (also known as POZ) was first identified as a conserved motif presented in the Drosophila melanogaster Bric-a-Brac, Tramtrack, Broad complex transcription regulators (1). BTB, Cul3 and RBX1 form a Cul3-based ligase (BCR), which targets substrates for ubiquitin-dependent degradation by the 26S proteasome. As a substrate recognition subunit of Cul3-based ligase, the member of BTB family can bridge the Cul3 to the substrate in a single polypeptide (2,3). Recently, it was observed that a 3-box is responsible for the Cul3-interacting in a variety of BTB proteins including almost all of BTB-Kelch and MATH-BTB proteins (4). Here we defined the BTB_Other family as the proteins contain only BTB domain but not 3-box domain. BTB-containing proteins are highly conserved and participate in diverse biological processes, including transcriptional regulation, ion channel assembly and gating, cytoskeleton dynamics, and targeting proteins for ubiquitination (1).

1. Stogios, P.J., Downs, G.S., Jauhal, J.J., Nandra, S.K. and Prive, G.G. (2005). Sequence and structural analysis of BTB domain proteins. Genome Biol., 6, R82. PMID:16207353

2. Xu, L., Wei, Y., Reboul, J., Vaglio, P., Shin, T.H., Vidal, M., Elledge, S.J. and Harper, J.W. (2003). BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature, 425, 316-321. PMID: 13679922

3. Pintard, L., Willems, A. and Peter, M. (2004). Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family. EMBO J., 23, 1681-1687. PMID: 15071497

4. Zhuang, M., Calabrese, M.F., Liu, J., Waddell, M.B., Nourse, A., Hammel, M., Miller, D.J., Walden, H., Duda, D.M., Seyedin, S.N., Hoggard, T., Harper, J. W., White, K. P. and Schulman, B. A.. (2009). Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol. Cell, 36(1): 39-50. PMID: 19818708

    Cullin family are a family of hydrophobic proteins that act as scaffolds for ubiquitin ligases. Cullin consists of several domains, including cullin repeat domain, a 4-helical bundle domain, an alpha+beta domain, and a winged helix-like domain. Members of Cullin family are found throughout eukaryotes. Humans express seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), each forming part of a multi-subunit ubiquitin complex. Cullin RING ubiquitin ligases (CRLs), such as Cul1 (SCF), play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose sensing and DNA replication to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzymes (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53 cytoplasmic anchor PARC; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact with specific adaptor proteins (1).

1. http://www.ebi.ac.uk/interpro/entry/IPR001373

    DDB1 represents "DNA damage-binding protein 1", a subunit of DCX (DDB1-CUL4-X-box) E3 ligase complex. Members of DDB1 family can recruit substrate-specific recognizing and binding adaptors to the DCX complex. The substrate-specific adaptors contain two main classes, DCAF (DDB1- and CUL4-associated factor) and WDR (WD40-repeat) proteins (1,2). As conserved in eukaryote, the DDB1-containting DCX complex is a Cullin-RING ubiquitin ligase that can regulate DNA replication and transcription, DNA repair, and can also be hijacked by pathogenic viruses to make for viral infection (3).

1. Lee, J. and Zhou, P. (2007). DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase. Mol. Cell, 26, 775-780. PMID: 17588513

2. Higa, L.A., Wu, M., Ye, T., Kobayashi, R., Sun, H. and Zhang, H. (2006). CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat Cell. Biol., 8, 1277-1283.PMID: 17041588

3. Angers, S., Li, T., Yi, X., MacCoss, M.J., Moon, R.T. and Zheng, N. (2006). Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature, 443, 590-593. PMID: 16964240

    DWD represents "DDB1-binding WD40 protein", a 16-residue motif as the subdomain of WD40 repeats (1). Members of DWD family can directly bind to the DDB1 and serve as the substrate recognition subunits of the DCX (DDB1-CUL4-X-box) E3 ligase complex, which display important functions in eukaryotic biology and in human diseases (2).

1. Jackson, S. and Xiong, Y. (2009). CRL4s: the CUL4-RING E3 ubiquitin ligases. Trends Biochem. Sci., 34, 562-570. PMID: 19818632

2. Angers, S., Li, T., Yi, X., MacCoss, M.J., Moon, R.T. and Zheng, N. (2006). Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature, 443, 590-593. PMID: 16964240

    Elon-B/C is a complex that comprises two subunits, named Elongin B and Elongin C. In the BCR ubiquitin ligase complex, a member of Elon-B/C family acts as an adaptor binding a substrate recognition subunit to heterodimer composed of either Cul2-Rbx1 or Cul5-Rbx2.

1. Piessevaux, J., De Ceuninck, L., Catteeuw, D., Peelman, F. & Tavernier, J. (2004). Elongin B/C recruitment regulates substrate binding by CIS. J. Biol. Chem.., 283(31): 21334-46. PMID: 15601820

    SOCS/VHL/BC-box represents a family that comprises SOCS proteins, VHL proteins and only BC-box containing proteins. The BC-box is a sub-domain that exists in both the SOCS and VHL domains and facilitates binding to the Elongin-B/C complex. SOCS is an ~80-residue domain named "Supressors Of Cytokine Signaling", which is located in the C-terminus and specifically recognize and bind a substrate. VHL is named "Von-Hippel Lindau", which forms the core of a large BCR E3 ubiquitin ligase complex. Compared to the SOCS domain, VHL lacks a C-terminal sequence (downstream of the BC-box) of the SOCS. VHL protein specifically interacts with endogenous Cul2-Rbx1 in mammalian cells. VHL or SOCS can serve as a substrate recognition subunit and form a BCR ubiquitin ligase complex, which targets the substrates for proteasome degradation (1).

1. Kamura, T., Maenaka, K., Kotoshiba, S., Matsumoto, M., Kohda, D., Conaway, R.C., Conaway, J.W. and Nakayama, K.I. (2004). VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes Dev., 18, 3055-3065. PMID: 15601820

    Cullin RING/Other/Other family is a unconventional E3 adaptor family that consists of miscellaneous non-classical domains containing substrate-specific adaptors, such as RICTOR, DCAF15, DCAF16, DCAF17, HOXB4, TRPC4AP, AHR, CRBN and so on.

    F-box is a protein structural motif of about 50 amino acids that was first found in cyclin F. F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the proteasome. The F-box motif interacts directly with the SCF protein Skp1, and F-box domains commonly exist in proteins in concert with other protein-protein interaction motifs such as leucine-rich repeats and WD repeats, which are thought to mediate interactions with SCF substrates. Members of F-box family mediate protein-protein interactions in a variety of contexts, such as polyubiquitination, transcription elongation, centromere binding and translational repression. In plants, many F-box proteins are represented in gene networks broadly regulated by microRNA-mediated gene silencing via RNA interference (1).

1. http://pfam.xfam.org/family/PF00646

    SKP1 is a structurally multi-helical domain found at the C-terminal of SKP1 proteins, as well as in subunit D of the centromere DNA-binding protein complex Cbf3. This domain consists of an interlocked herterodimer in F-box proteins. SKP1 (together with SKP2) was identified as an essential component of the cyclin A-CDK2 S phase kinase complex. Now it is thought as a adaptor that connects cullin1 and F-box containing protein and involves in the ubiquitin pathway (1).

1. http://pfam.xfam.org/family/Skp1