SMART: UBCc domain annotation

UBCc Ubiquitin-conjugating enzyme E2, catalytic domain homologues

SMART accession number:	SM00212
Description:	Proteins destined for proteasome-mediated degradation may be ubiquitinated. Ubiquitination follows conjugation of ubiquitin to a conserved cysteine residue of UBC homologues. This pathway functions in regulating many fundamental processes required for cell viability.TSG101 is one of several UBC homologues that lacks this active site cysteine.
Interpro abstract (IPR000608):	The post-translational attachment of ubiquitin (IPR000626) to proteins (ubiquitinylation) alters the function, location or trafficking of a protein, or targets it to the 26S proteasome for degradation (PUBMED:15556404), (PUBMED:15196553), (PUBMED:15454246). Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1, IPR000011), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3, IPR000569, IPR003613), which work sequentially in a cascade (PUBMED:14998368). The E1 enzyme mediates an ATP-dependent transfer of a thioester-linked ubiquitin molecule to a cysteine residue on the E2 enzyme. The E2 enzyme (EC 6.3.2.19) then either transfers the ubiquitin moiety directly to a substrate, or to an E3 ligase, which can also ubiquitinylate a substrate. There are several different E2 enzymes (over 30 in humans), which are broadly grouped into four classes, all of which have a core catalytic domain (containing the active site cysteine), and some of which have short N- and C-terminal amino acid extensions: class I enzymes consist of just the catalytic core domain (UBC), class II possess a UBC and a C-terminal extension, class III possess a UBC and an N-terminal extension, and class IV possess a UBC and both N- and C-terminal extensions. These extensions appear to be important for some subfamily function, including E2 localisation and protein-protein interactions (PUBMED:15545318). In addition, there are proteins with an E2-like fold that are devoid of catalytic activity, but which appear to assist in poly-ubiquitin chain formation.
GO process:	regulation of protein metabolic process (GO:0051246), post-translational protein modification (GO:0043687)
GO function:	small conjugating protein ligase activity (GO:0019787)
Family alignment:	View or

There are 3029 UBCc domains in 3020 proteins in SMART's nrdb database.

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Evolution (species in which this domain is found)
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This tree shows only several representative species. The complete taxonomic breakdown of all proteins with UBCc domain is also avaliable.

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Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes
Cellular role (predicted cellular role)
Binding / catalysis: protein-binding, ubiquitin-conjugating
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Cook WJ, Martin PD, Edwards BF, Yamazaki RK, Chau V
- Crystal structure of a class I ubiquitin conjugating enzyme (Ubc7) from Saccharomyces cerevisiae at 2.9 angstroms resolution.
- Biochemistry. 1997; 36: 1621-7
- Display abstract
- Ubiquitin-conjugating enzymes are a family of related proteins that participate in the ubiquitination of proteins. Previous studies on the crystal structures of Saccharomyces cerevisiae Ubc4 and Arabidopsis thaliana Ubc1 indicated that the smallest enzymes (class I), which consist entirely of the conserved core domain, share a common tertiary fold. Here we report the three-dimensional structure of the S. cerevisiae class I enzyme encoded by the UBC7 gene. The crystal structure has been solved using molecular replacement techniques and refined by simulated annealing to an R-factor of 0.183 at 2.93 A resolution. Bond lengths and angles in the molecule have root-mean-square deviations from ideal values of 0.016 A and 2.3 degrees, respectively. Ubc7 is an alpha/beta protein with four alpha-helices and a four-stranded antiparallel beta-sheet. With the exception of two regions where extra residues are present, the tertiary folding of Ubc7 is similar to those of the other two enzymes. The ubiquitin-accepting cysteine is located in a cleft between two loops. One of these loops is nonconserved, as this region of the Ubc7 molecule differs from the other two enzymes by having 13 extra residues. There is also a second single amino acid insertion that alters the orientation of the turn between the first two beta-strands. Analysis of the 13 ubiquitin-conjugating enzyme sequences in S. cerevisiae indicates that there may be two other regions where extra residues could be inserted into the common tertiary fold. Both of these other regions exhibit significant deviations in the superposition of the three structures and, like the two insertion regions in Ubc7, may represent hypervariable regions within a common tertiary fold. As ubiquitin-conjugating enzymes interact with different substrates or other accessory proteins in the ubiquitination pathway, these variable surface regions may confer distinct specificity to individual enzymes.
- Hatakeyama S, Jensen JP, Weissman AM
- Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases.
- J Biol Chem. 1997; 272: 15085-92
- Display abstract
- In most instances, the transfer of ubiquitin to target proteins is catalyzed by the action of ubiquitin protein ligases (E3s). Full-length cDNAs encoding murine E6-associated protein (mE6-AP) as well as Nedd-4, a protein that is homologous to E6-AP in its C terminus, were cloned. Nedd-4 and mouse E6-AP are both enzymatically active E3s and function with members of the UbcH5 family of E2s. Mouse E6-AP, like its human counterpart, ubiquitinates p53 in the presence of human papilloma virus E6 protein, while Nedd-4 does not. Consistent with its role in p53 ubiquitination, mE6-AP was found both in the nucleus and cytosol, while Nedd-4 was found only in the cytosol. Binding studies implicate a 150-amino acid region that is 40% identical between mE6-AP and Nedd-4 as a binding site for the C-terminal portion of an E2 enzyme (UbcH5B). Nedd-4 was determined to have a second nonoverlapping E2 binding site that recognizes the first 67 amino acids of UbcH5B but not the more C-terminal portion of this E2. These findings provide the first demonstration of physical interactions between mammalian E2s and E3s and establish that these interactions occur independently of ubiquitin and an intact E3 catalytic domain. Furthermore, the presence of two E2 binding sites within Nedd-4 suggests models for ubiquitination involving multiple E2 enzymes associated with E3s.
- Koonin EV, Abagyan RA
- TSG101 may be the prototype of a class of dominant negative ubiquitin regulators.
- Nat Genet. 1997; 16: 330-1
- Kumar S, Kao WH, Howley PM
- Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity.
- J Biol Chem. 1997; 272: 13548-54
- Display abstract
- The cellular protein E6AP functions as an E3 ubiquitin protein ligase in the E6-dependent ubiquitination of p53. E6AP is a member of a family of functionally related E3 proteins that share a conserved carboxyl-terminal region called the Hect domain. Although several different E2 ubiquitin-conjugating enzymes have been shown to function with E6AP in the E6-dependent ubiquitination of p53 in vitro, the E2s that cooperate with E6AP in the ubiquitination of its normal substrates are presently unknown. Moreover, the basis of functional cooperativity between specific E2 and Hect E3 proteins has not yet been determined. Here we report the cloning of a new human E2, designated UbcH8, that was identified in a two-hybrid screen through specific interaction with E6AP. We demonstrate that UbcH7, an E2 closely related to UbcH8, can also bind to E6AP. The region of E6AP involved in complex formation with UbcH8 and UbcH7 was mapped to its Hect domain. Furthermore, we show that UbcH5 and UbcH6, two highly homologous E2s that were deficient for interaction with E6AP, could associate efficiently with another Hect-E3 protein, RSP5. Finally, only the E6AP-interacting E2s could function in conjunction with E6AP in the ubiquitination of an E6 independent substrate of E6AP, whereas the noninteracting E2s could not. Taken together, these studies demonstrate for the first time complex formation between specific human E2s and the Hect domain family of E3 proteins and suggest that selective physical interaction between E2 and E3 enzymes forms the basis of specificity for functionally distinct E2:E3 combinations.
- Ponting CP, Aravind L
- PAS: a multifunctional domain family comes to light.
- Curr Biol. 1997; 7: 6747-6747
- Ponting CP, Cai YD, Bork P
- The breast cancer gene product TSG101: a regulator of ubiquitination?
- J Mol Med. 1997; 75: 467-9
- Display abstract
- Sequence analysis is a powerful tool to obtain structural and functional information about genes and their products. Here we show that TSG101, a gene subjected to somatic mutations in breast cancer, contains an amino terminal domain that is a homologue of ubiquitin conjugating enzymes (UBCs) and not, as previously proposed, DNA-binding domains. As the UBC active site residue is replaced in the TSG101 sequence in a similar manner to several other members of the UBC family, we propose a role for TSG101 in regulating the ubiquitination of short-lived gene products.
- Cook WJ, Jeffrey LC, Xu Y, Chau V
- Tertiary structures of class I ubiquitin-conjugating enzymes are highly conserved: crystal structure of yeast Ubc4.
- Biochemistry. 1993; 32: 13809-17
- Display abstract
- The three-dimensional structure of a yeast ubiquitin-conjugating enzyme, encoded by the Saccharomyces cerevisiae UBC4 gene, has been determined at 2.7 A. The structure was solved using molecular replacement techniques and refined by simulated annealing to an R-factor of 0.198. Bond lengths and angles in the molecule have root mean square deviations from ideal values of 0.018 A and 4.0 degrees, respectively. Ubc4 is an alpha/beta protein with four alpha-helices and a four-stranded antiparallel beta-sheet. The ubiquitin-accepting cysteine is located in a cleft between two loops. Comparison with the recently determined structure of a different plant enzyme suggests that class I ubiquitin-conjugating enzymes are highly conserved in their three-dimensional folding. Except for two extra residues at the N- and the C-terminus of the plant enzyme, the C alpha atoms of the two enzymes can be superimposed with a root mean square deviation of only 1.52 A. Greater variations are found between the surfaces of the two molecules, as most of the identical residues between the two enzymes are either buried or clustered on the surface that lies adjacent to the ubiquitin-accepting cysteine. We suggest that this conserved surface functions in protein-protein binding during ubiquitin thiol ester formation.
- Cook WJ, Jeffrey LC, Sullivan ML, Vierstra RD
- Three-dimensional structure of a ubiquitin-conjugating enzyme (E2).
- J Biol Chem. 1992; 267: 15116-21
- Display abstract
- The x-ray crystal structure of a recombinant ubiquitin-conjugating enzyme (E2) encoded by the UBC1 gene of the plant Arabidopsis thaliana has been determined with the use of multiple isomorphous replacement techniques and refined at 2.4-A resolution by simulated annealing and restrained least-squares. This E2 is an alpha/beta protein, with four alpha-helices and a four-stranded antiparallel beta-sheet. The NH2 and COOH termini, which may be important for interaction with other enzymes and substrates in the ubiquitin-conjugation pathway, are on the opposite side of the molecule from the cysteine residue that binds to the COOH terminus of ubiquitin. This structure should now allow for the rational analysis of E2 function by in vitro mutagenesis and facilitate the effective design of E2s with unique specificities or catalytic functions.
Metabolism (metabolic pathways involving proteins which contain this domain)

Structure (3D structures containing this domain)

3D Structures of UBCc domains in PDB

PDB code	Main view	Title
1a3s		Human ubc9
1ayz		Crystal structure of the saccharomyces cerevisiae ubiquitin- conjugating enzyme rad6 (ubc2) at 2.6a resolution
1c4z		Structure of e6ap: insights into ubiquitination pathway
1fbv		Structure of a cbl-ubch7 complex: ring domain function in ubiquitin-protein ligases
1fxt		Structure of a conjugating enzyme-ubiquitin thiolester complex
1fzy		Crystal structure of saccharomyces cerevisiae ubiquitin conjugating enzyme 1
1i7k		Crystal structure of human mitotic-specific ubiquitin- conjugating enzyme, ubch10
1j74		Crystal structure of mms2
1j7d		Crystal structure of hmms2-hubc13
1jas		Hsubc2b
1jat		Mms2/ubc13 ubiquitin conjugating enzyme complex
1jbb		Ubiquitin conjugating enzyme, ubc13
1kpp		Structure of the tsg101 uev domain
1kpq		Structure of the tsg101 uev domain
1kps		Structural basis for e2-mediated sumo conjugation revealed by a complex between ubiquitin conjugating enzyme ubc9 and rangap1
1m4p		Structure of the tsg101 uev domain in complex with a hiv-1 ptap "late domain" peptide, dyana ensemble
1m4q		Structure of the tsg101 uev domain in complex with a hiv-1 ptap "late domain" peptide, cns ensemble
1pzv		Crystal structures of two ubc (e2) enzymes of the ubiquitin- conjugating system in caenorhabditis elegans
1q34		Crystal structures of two ubc (e2) enzymes of the ubiquitin- conjugating system in caenorhabditis elegans
1qcq		Ubiquitin conjugating enzyme
1s1q		Tsg101(uev) domain in complex with ubiquitin
1tte		The structure of a class ii ubiquitin-conjugating enzyme, ubc1.
1u9a		Human ubiquitin-conjugating enzyme ubc9
1u9b		Murine/human ubiquitin-conjugating enzyme ubc9
1ur6		Nmr based structural model of the ubch5b-cnot4 complex
1uzx		A complex of the vps23 uev with ubiquitin
1w4u		Nmr solution structure of the ubiquitin conjugating enzyme ubch5b
1wzv		Crystal structure of ubch8
1wzw		Crystal structure of ubch8
1x23		Crystal structure of ubch5c
1y6l		Human ubiquitin conjugating enzyme e2e2
1y8x		Structural basis for recruitment of ubc12 by an e2-binding domain in nedd8's e1
1yf9		Structural analysis of leishmania major ubiquitin conjugating enzyme e2
1yh2		Ubiquitin-conjugating enzyme hspc150
1yla		Ubiquitin-conjugating enzyme e2-25 kda (huntington interacting protein 2)
1yrv		Novel ubiquitin-conjugating enzyme
1z2u		The 1.1a crystallographic structure of ubiquitin- conjugating enzyme (ubc-2) from caenorhabditis elegans: functional and evolutionary significance
1z3d		Protein crystal growth improvement leading to the 2.5a crystallographic structure of ubiquitin-conjugating enzyme (ubc-1) from caenorhabditis elegans
1z5s		Crystal structure of a complex between ubc9, sumo-1, rangap1 and nup358/ranbp2
1zdn		Ubiquitin-conjugating enzyme e2s
1zgu		Solution structure of the human mms2-ubiquitin complex
1zuo		Structure of human ubiquitin-conjugating enzyme (ubci) involved in embryo attachment and implantation
2a4d		Structure of the human ubiquitin-conjugating enzyme e2 variant 1 (uev-1)
2a7l		Structure of the human hypothetical ubiquitin-conjugating enzyme, loc55284
2aak		Ubiquitin conjugating enzyme from arabidopsis thaliana
2awf		Structure of human ubiquitin-conjugating enzyme e2 g1
2ayv		Crystal structure of a putative ubiquitin-conjugating enzyme e2 from toxoplasma gondii
2bep		Crystal structure of ubiquitin conjugating enzyme e2-25k
2bf8		Crystal structure of sumo modified ubiquitin conjugating enzyme e2-25k
2c2v		Crystal structure of the chip-ubc13-uev1a complex
2c4o		Crystal structure of human ubiquitin-conjugating enzyme ubch5b
2c4p		Crystal structure of human ubiquitin-conjugating enzyme ubch5a
2clw		Crystal structure of human ubiquitin-conjugating enzyme ubch5b
2cyx		Structure of human ubiquitin-conjugating enzyme e2 g2 (ube2g2/ubc7)
2e2c		E2-c, an ubiquitin conjugating enzyme required for the destruction of mitotic cyclins
2edi		Solution structure of the uq_con domain from human nedd8- conjugating enzyme nce2
2eke		Structure of a sumo-binding-motif mimic bound to smt3p- ubc9p: conservation of a noncovalent ubiquitin-like protein-e2 complex as a platform for selective interactions within a sumo pathway
2esk		Human ubiquitin-conjugating enzyme (e2) ubch5b, wild-type
2eso		Human ubiquitin-conjugating enzyme (e2) ubch5b mutant ile37ala
2esp		Human ubiquitin-conjugating enzyme (e2) ubch5b mutant ile88ala
2esq		Human ubiquitin-conjugating enzyme (e2) ubch5b mutant ser94gly
2f0r		Crystallographic structure of human tsg101 uev domain
2f4w		Human ubiquitin-conjugating enzyme e2 j2
2f4z		Toxoplasma gondii ubiquitin conjugating enzyme tgtwinscan_2721- e2 domain
2fo3		Plasmodium vivax ubiquitin conjugating enzyme e2
2fuh		Solution structure of the ubch5c/ub non-covalent complex
2gjd		Distinct functional domains of ubc9 dictate cell survival and resistance to genotoxic stress
2gmi		Mms2/ubc13~ubiquitin
2grn		Crystal structure of human rangap1-ubc9
2gro		Crystal structure of human rangap1-ubc9-n85q
2grp		Crystal structure of human rangap1-ubc9-y87a
2grq		Crystal structure of human rangap1-ubc9-d127a
2grr		Crystal structure of human rangap1-ubc9-d127s
2h2y		Crystal structure of ubiquitin conjugating enzyme e2 from plasmodium falciparum
2hlw		Solution structure of the human ubiquitin-conjugating enzyme variant uev1a
2nvu		Structure of appbp1-uba3~nedd8-nedd8-mgatp-ubc12(c111a), a trapped ubiquitin-like protein activation complex
2o25		Ubiquitin-conjugating enzyme e2-25 kda complexed with sumo- 1-conjugating enzyme ubc9
2ob4		Human ubiquitin-conjugating enzyme cdc34
2onu		Plasmodium falciparum ubiquitin conjugating enzyme pf10_0330, putative homologue of human ube2h
2oxq		Structure of the ubch5 :chip u-box complex
2pe6		Non-covalent complex between human sumo-1 and human ubc9
2pwq		Crystal structure of a putative ubiquitin conjugating enzyme from plasmodium yoelii
2px9		The intrinsic affinity between e2 and the cys domain of e1 in ubiquitin-like modifications
2q0v		Crystal structure of ubiquitin conjugating enzyme e2, putative, from plasmodium falciparum
2qgx		Ubiquitin-conjugating enzyme e2q
2r0j		Crystal structure of the putative ubiquitin conjugating enzyme, pfe1350c, from plasmodium falciparum
2ucz		Ubiquitin conjugating enzyme (ubc7) from saccharomyces cerevisiae
2uyz		Non-covalent complex between ubc9 and sumo1
2vrr		Structure of sumo modified ubc9
2z5d		Human ubiquitin-conjugating enzyme e2 h
3a33
3bzh		Crystal structure of human ubiquitin-conjugating enzyme e2 e1
3ceg		Crystal structure of the ubc domain of baculoviral iap repeat-containing protein 6
3e46
3e95
3eb6
3f92
3fn1
3fsh
3h8k
3hct
3hcu

Links (links to other resources describing this domain)
BLOCKS UBIQUITIN_CONJUGAT
PFAM UQ_con
INTERPRO IPR000608

BLOCKS	UBIQUITIN_CONJUGAT
PFAM	UQ_con
INTERPRO	IPR000608