Summary: Ubiquitin-conjugating enzyme

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Wikipedia: Ubiquitin-conjugating enzyme
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Ubiquitin-conjugating enzyme Edit Wikipedia article

Ubiquitin—protein ligase

Identifiers

Databases

PDB structures

Search
PMC	articles
PubMed	articles
NCBI	proteins

Ubiquitin-conjugating enzyme, E2

Identifiers

Symbol

UBQ-conjugat_E2

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

Relationships

A ubiquitin-activating enzyme, or E1, first activates the ubiquitin by covalently attaching the molecule to its active site cysteine residue. The activated ubiquitin is then transferred to an E2 cysteine. Once conjugated to ubiquitin, the E2 molecule binds one of several ubiquitin ligases or E3s via a structurally conserved binding region. The E3 molecule is responsible for binding the target protein substrate and transferring the ubiquitin from the E2 cysteine to a lysine residue on the target protein.^[1]

Schematic diagram of the ubiquitylation system.

A particular cell usually contains only a few types of E1 molecule, a greater diversity of E2s, and a very large variety of E3s. The E3 molecules responsible for substrate identification and binding are thus the mechanisms of substrate specificity in proteasomal degradation. Each type of E2 can associate with many E3s.^[2]

Isozymes

The following human genes encode ubiquitin-conjugating enzymes:

UBE2A
UBE2B
UBE2C
UBE2D1, UBE2D2, UBE2D3, UBE2D4 (the latter putative)
UBE2E1, UBE2E2, UBE2E3
UBE2F (putative)
UBE2G1, UBE2G2
UBE2H
UBE2I
UBE2J1, UBE2J2
UBE2K
UBE2L3, UBE2L6; (UBE2L1, UBE2L2, UBE2L4 are pseudogenes)
UBE2M
UBE2N
UBE2O
UBE2Q1, UBE2Q2
UBE2R1 (CDC34), UBE2R2
UBE2S
UBE2T (putative)
UBE2U (putative)
UBE2V1, UBE2V2
UBE2W (putative)
UBE2Z
ATG3
BIRC6
UFC1

References

^ Nandi D, Tahiliani P, Kumar A, Chandu D (2006). "The ubiquitin-proteasome system". Journal of biosciences. 31 (1): 137–55. PMID 16595883. doi:10.1007/BF02705243.
^ Risseeuw EP, Daskalchuk TE, Banks TW, Liu E, Cotelesage J, Hellmann H, Estelle M, Somers DE, Crosby WL (2003). "Protein interaction analysis of SCF ubiquitin E3 ligase subunits from Arabidopsis". The Plant journal : for cell and molecular biology. 34 (6): 753–67. PMID 12795696. doi:10.1046/j.1365-313X.2003.01768.x.

External links

Eukaryotic Linear Motif resource motif class MOD_SUMO
Ubiquitin-Conjugating Enzymes at the US National Library of Medicine Medical Subject Headings (MeSH)

Posttranslational modification

Chaperones/
protein folding

Heat shock proteins/ Chaperonins	Hsp10/GroES Hsp27 Hsp47 HSP60/GroEL Hsp40/DnaJ A1 A2 A3 B1 B2 B11 B4 B6 B9 C1 C3 C5 C6 C7 C10 C11 C13 C14 C19 Hsp70 1A 1B 1L 2 4 4L 5 6 7 8 9 12A 14 Hsp90 α₁ α₂ β ER TRAP1
Other	Alpha crystallin Clusterin Survival of motor neuron SMN1 SMN2

Protein targeting

Ubiquitin

E1 Ubiquitin-activating enzyme
- UBA1
- UBA2
- UBA3
- UBA5
- UBA6
- UBA7
- ATG7
- NAE1
- SAE1

E2 Ubiquitin-conjugating enzyme
- A
- B
- C
- D1
- D2
- D3
- E1
- E2
- E3
- G1
- G2
- H
- I
- J1
- J2
- K
- L1
- L2
- L3
- L4
- L6
- M
- N
- O
- Q1
- Q2
- R1 (CDC34)
- R2
- S
- V1
- V2
- Z

E3 Ubiquitin ligase
- VHL
- Cullin
- CBL
- MDM2
- FANCL
- UBR1

Other

Ubiquitin-like modifiers
- SUMO protein
- ISG15
- URM1
- NEDD8
- FAT10
- ATG8
- ATG12
- FUB1
- MUB
- UFM1
- UBL5
Prokaryotic ubiquitin-like protein

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Ubiquitin-conjugating enzyme Provide feedback

Proteins destined for proteasome-mediated degradation may be ubiquitinated. Ubiquitination follows conjugation of ubiquitin to a conserved cysteine residue of UBC homologues. TSG101 is one of several UBC homologues that lacks this active site cysteine [4, 5].

Literature references

Cook WJ, Jeffrey LC, Sullivan ML, Vierstra RD; , J Biol Chem 1992;267:15116-15121.: Three-dimensional structure of a ubiquitin-conjugating enzyme (E2). PUBMED:1321826 EPMC:1321826
Cook WJ, Jeffrey LC, Xu Y, Chau V; , Biochemistry 1993;32:13809-13817.: Tertiary structures of class I ubiquitin-conjugating enzymes are highly conserved: crystal structure of yeast Ubc4. PUBMED:8268156 EPMC:8268156
Cook WJ, Martin PD, Edwards BF, Yamazaki RK, Chau V; , Biochemistry 1997;36:1621-1627.: Crystal structure of a class I ubiquitin conjugating enzyme (Ubc7) from Saccharomyces cerevisiae at 2.9 angstroms resolution. PUBMED:9048545 EPMC:9048545
Koonin EV, Abagyan RA; , Nat Genet 1997;16:330-331.: TSG101 may be the prototype of a class of dominant negative ubiquitin regulators. PUBMED:9241264 EPMC:9241264
Ponting CP, Cai YD, Bork P , J Mol Med 1997;75:467-469.: The breast cancer gene product TSG101: a regulator of ubiquitination? PUBMED:9253709 EPMC:9253709
Burroughs AM, Jaffee M, Iyer LM, Aravind L;, J Struct Biol. 2008;162:205-218.: Anatomy of the E2 ligase fold: implications for enzymology and evolution of ubiquitin/Ub-like protein conjugation. PUBMED:18276160 EPMC:18276160

Internal database links

SCOOP:	Prok-E2_B RWD UEV UFC1
Similarity to PfamA using HHSearch:	UEV UFC1 Prok-E2_B

External database links

HOMSTRAD:	uce
PROSITE:	PDOC00163
SCOP:	1aak
SMART:	UBCc

This tab holds annotation information from the InterPro database.

InterPro entry IPR000608

Ubiquitin-conjugating enzymes (UBC or E2 enzymes) [PUBMED:2193438, PUBMED:1647207, PUBMED:1656558] catalyse the covalent attachment of ubiquitin to target proteins. Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1, INTERPRO), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3, INTERPRO, INTERPRO), 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) 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 (such as protein crossbronx from flies), but which appear to assist in poly-ubiquitin chain formation.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan UBC (CL0208), which has the following description:

This superfamily includes a diverse set of proteins that bind to ubiquitin [1].

The clan contains the following 10 members:

Knl1_RWD_C Prok-E2_A Prok-E2_B Prok-E2_C Prok-E2_D Prok-E2_E RWD UEV UFC1 UQ_con

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
UniProt: alignment generated by searching the UniProtKB sequence database using the family HMM
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

Selex
Stockholm
FASTA
MSF

You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

	Seed (65)	Full (30654)	Representative proteomes				UniProt (44040)	NCBI (46265)	Meta (315)
	Seed (65)	Full (30654)	RP15 (8243)	RP35 (16631)	RP55 (24020)	RP75 (29325)	UniProt (44040)	NCBI (46265)	Meta (315)
Jalview	View	View	View	View	View	View	View	View	View
HTML	View
PP/heatmap	₁

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (65)	Full (30654)	Representative proteomes				UniProt (44040)	NCBI (46265)	Meta (315)
	Seed (65)	Full (30654)	RP15 (8243)	RP35 (16631)	RP55 (24020)	RP75 (29325)	UniProt (44040)	NCBI (46265)	Meta (315)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (65)	Full (30654)	Representative proteomes				UniProt (44040)	NCBI (46265)	Meta (315)
	Seed (65)	Full (30654)	RP15 (8243)	RP35 (16631)	RP55 (24020)	RP75 (29325)	UniProt (44040)	NCBI (46265)	Meta (315)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

Prosite

Previous IDs:

none

Type:

Domain

Sequence Ontology:

SO:0000417

Author:

Ponting CP

, Schultz J, Bork P

, Finn RD

Number in seed:

65

Number in full:

30654

Average length of the domain:

132.40 aa

Average identity of full alignment:

27 %

Average coverage of the sequence by the domain:

43.74 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	21.3	21.3
Trusted cut-off	21.3	21.3
Noise cut-off	21.2	21.2

Model length:

140

Family (HMM) version:

26

Download:

download the raw HMM for this family

Species distribution

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Colour assignments

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 35 interactions for this family. More...

Peroxin-22 zf-C3HC4_2 E1_UFD UBA_e1_thiolCys Rad60-SLD SopA_C ubiquitin Cbl_N2 IBN_N Xpo1 Rad60-SLD zf-A20 UBA SopA RanGAP1_C UBA ubiquitin HECT zf-RING_2 zf-C3HC4_3 HECT zf-RING_4 Peptidase_C65 zf-C3HC4 Peptidase_C65 zf-RING_2 UQ_con zf-C3HC4_3 U-box E2_bind zf-C3HC4 ThiF E2_bind IR1-M RanGAP1_C

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the UQ_con domain has been found. There are 411 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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Family: UQ_con (PF00179)

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