Summary: SET domain
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "SET domain". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at firstname.lastname@example.org and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
SET domain Edit Wikipedia article
structure and substrate of a histone h3 lysine methyltransferase from paramecium bursaria chlorella virus 1
The SET domain is a protein domain. It was originally identified as part of a larger conserved region present in the Drosophila Trithorax protein and was subsequently identified in the Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins, from which the acronym SET is derived [Su(var)3-9, Enhancer-of-zeste and Trithorax].
- Neurospora crassa DIM-5, a member of the Su(var) family of HKMTs which methylate histone H3 on lysine 9,
- human SET7 (also called SET9), which methylates H3 on lysine 4
- garden pea Rubisco LSMT, an enzyme that does not modify histones, but instead methylates lysine 14 in the flexible tail of the large subunit of the enzyme Rubisco.
The SET domain itself turned out to be an uncommon structure. Although in all three studies, electron density maps revealed the location of the AdoMet or AdoHcy cofactor, the SET domain bears no similarity at all to the canonical/AdoMet-dependent methyltransferase fold. Strictly conserved in the C-terminal motif of the SET domain tyrosine could be involved in abstracting a proton from the protonated amino group of the substrate lysine, promoting its nucleophilic attack on the sulphonium methyl group of the AdoMet cofactor. In contrast to the AdoMet-dependent protein methyltranferases of the classical type, which tend to bind their polypeptide substrates on top of the cofactor, it is noted from the Rubisco LSMT structure that the AdoMet seems to bind in a separate cleft, suggesting how a polypeptide substrate could be subjected to multiple rounds of methylation without having to be released from the enzyme. In contrast, SET7/9 is able to add only a single methyl group to its substrate.
It has been demonstrated that association of SET domain and myotubularin-related proteins modulates growth control. The SET domain-containing Drosophila melanogaster (Fruit fly) protein, enhancer of zeste, has a function in segment determination and the mammalian homologue may be involved in the regulation of gene transcription and chromatin structure.
Histone lysine methylation is part of the histone code that regulated chromatin function and epigenetic control of gene function. Histone lysine methyltransferases (HMTase) differ both in their substrate specificity for the various acceptor lysines as well as in their product specificity for the number of methyl groups (one, two, or three) they transfer. With just one exception, the HMTases belong to SET family that can be classified according to the sequences surrounding the SET domain. Structural studies on the human SET7/9, a mono-methylase, have revealed the molecular basis for the specificity of the enzyme for the histone-target and the roles of the invariant residues in the SET domain in determining the methylation specificities.
The pre-SET domain, as found in the SUV39 SET family, contains nine invariant cysteine residues that are grouped into two segments separated by a region of variable length. These 9 cysteines coordinate 3 zinc ions to form a triangular cluster, where each of the zinc ions is coordinated by 4 four cysteines to give a tetrahedral configuration. The function of this domain is structural, holding together 2 long segments of random coils.
The C-terminal region including the post-SET domain is disordered when not interacting with a histone tail and in the absence of zinc. The three conserved cysteines in the post-SET domain form a zinc-binding site when coupled to a fourth conserved cysteine in the knot-like structure close to the SET domain active site. The structured post-SET region brings in the C-terminal residues that participate in S-adenosyl-L-methionine-binding and histone tail interactions. The three conserved cysteine residues are essential for HMTase activity, as replacement with serine abolishes HMTase activity.
Human genes encoding proteins containing this domain include:
- ASH1L, also has an associated with SET domain (AWS)
- EHMT1, EHMT2, EZH1, EZH2
- MLL, MLL2, MLL3, MLL5
- PRDM1, PRDM2, PRDM5
- SETD1A, SETD2, SETD3, SETD4, SETD5, SETD6, SETD7, SETD8, SETDB1, SETDB2, SETMAR, SMYD1, SMYD3, SMYD4, SMYD5, SUV39H1, SUV39H2,
- Cui X; De Vivo I; Slany R; Miyamoto A; Firestein R; Cleary ML (April 1998). "Association of SET domain and myotubularin-related proteins modulates growth control". Nat. Genet. 18 (4): 331–7. doi:10.1038/ng0498-331. PMID 9537414.
- Feng Q; Wang H; Ng HH; Erdjument-Bromage H; Tempst P; Struhl K; Zhang Y (June 2002). "Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain". Curr. Biol. 12 (12): 1052–8. doi:10.1016/S0960-9822(02)00901-6. PMID 12123582.
- Baumbusch LO; Thorstensen T; Krauss V; Fischer A; Naumann K; Assalkhou R; Schulz I; Reuter G; Aalen RB (November 2001). "The Arabidopsis thaliana genome contains at least 29 active genes encoding SET domain proteins that can be assigned to four evolutionarily conserved classes". Nucleic Acids Res. 29 (21): 4319–33. doi:10.1093/nar/29.21.4319. PMC . PMID 11691919.
- Kouzarides T (April 2002). "Histone methylation in transcriptional control". Curr. Opin. Genet. Dev. 12 (2): 198–209. doi:10.1016/S0959-437X(02)00287-3. PMID 11893494.
- Xiao B; Jing C; Wilson JR; Walker PA; Vasisht N; Kelly G; Howell S; Taylor IA; Blackburn GM; Gamblin SJ (February 2003). "Structure and catalytic mechanism of the human histone methyltransferase SET7/9". Nature. 421 (6923): 652–6. doi:10.1038/nature01378. PMID 12540855.
- Zhang X; Yang Z; Khan SI; Horton JR; Tamaru H; Selker EU; Cheng X (July 2003). "Structural basis for the product specificity of histone lysine methyltransferases". Mol. Cell. 12 (1): 177–85. doi:10.1016/S1097-2765(03)00224-7. PMC . PMID 12887903.
- Zhang X; Tamaru H; Khan SI; Horton JR; Keefe LJ; Selker EU; Cheng X (October 2002). "Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase". Cell. 111 (1): 117–27. doi:10.1016/S0092-8674(02)00999-6. PMC . PMID 12372305.
- Min J; Zhang X; Cheng X; Grewal SI; Xu RM (November 2002). "Structure of the SET domain histone lysine methyltransferase Clr4". Nat. Struct. Biol. 9 (11): 828–32. doi:10.1038/nsb860. PMID 12389037.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
SET domain Provide feedback
SET domains are protein lysine methyltransferase enzymes. SET domains appear to be protein-protein interaction domains. It has been demonstrated that SET domains mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases) . A subset of SET domains have been called PR domains. These domains are divergent in sequence from other SET domains, but also appear to mediate protein-protein interaction . The SET domain consists of two regions known as SET-N and SET-C. SET-C forms an unusual and conserved knot-like structure of probably functional importance. Additionally to SET-N and SET-C, an insert region (SET-I) and flanking regions of high structural variability form part of the overall structure .
Tripoulas N, LaJeunesse D, Gildea J, Shearn A; , Genetics 1996;143:913-928.: The Drosophila ash1 gene product, which is localized at specific sites on polytene chromosomes, contains a SET domain and a PHD finger. PUBMED:8725238 EPMC:8725238
Cui X, De Vivo I, Slany R, Miyamoto A, Firestein R, Cleary ML; , Nat Genet 1998;18:331-337.: Association of SET domain and myotubularin-related proteins modulates growth control. PUBMED:9537414 EPMC:9537414
Huang S, Shao G, Liu L; , J Biol Chem 1998;273:15933-15939.: The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin-mediated gene expression. PUBMED:9632640 EPMC:9632640
Internal database links
|SCOOP:||PHD SSXRD zf-MYND|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001214
The SET domain is a 130 to 140 amino acid, evolutionary well conserved sequence motif that was initially characterised in the Drosophila proteins Su(var)3-9, Enhancer-of-zeste and Trithorax. In addition to these chromosomal proteins modulating gene activities and/or chromatin structure, the SET domain is found in proteins of diverse functions ranging from yeast to mammals, but also including some bacteria and viruses [PUBMED:9487389, PUBMED:10949293].
The SET domains of mammalian SUV39H1 and 2 and fission yeast clr4 have been shown to be necessary for the methylation of lysine-9 in the histone H3 N terminus [PUBMED:10949293]. However, this histone methyltransferase (HMTase) activity is probably restricted to a subset of SET domain proteins as it requires the combination of the SET domain with the adjacent cysteine-rich regions, one located N-terminally (pre-SET) and the other posterior to the SET domain (post-SET). Post- and pre- SET regions seem then to play a crucial role when it comes to substrate recognition and enzymatic activity [PUBMED:12826405, PUBMED:12372294].
The structure of the SET domain and the two adjacent regions pre-SET and post-SET have been solved [PUBMED:12372305, PUBMED:12372304, PUBMED:12372303]. The SET structure is all beta, but consists only in sets of few short strands composing no more than a couple of small sheets. Consequently the SET structure is mostly defined by turns and loops. An unusual feature is that the SET core is made up of two discontinual segments of the primary sequence forming an approximate L shape [PUBMED:9632640, PUBMED:12826405, PUBMED:12372294]. Two of the most conserved motifs in the SET domain are constituted by (1) a stretch at the C-terminal containing a strictly conserved tyrosine residue and (2) a preceding loop inside which the C-terminal segment passes forming a knot-like structure, but not quite a true knot. These two regions have been proven to be essential for SAM binding and catalysis, particularly the invariant tyrosine where in all likelihood catalysis takes place [PUBMED:12826405, PUBMED:12372294].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||protein binding (GO:0005515)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
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.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- 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
- 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.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
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.
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.
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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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...
If you find these logos useful in your own work, please consider citing the following article:
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.
|Author:||Bateman A, Huang S|
|Number in seed:||257|
|Number in full:||20649|
|Average length of the domain:||162.00 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||22.33 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||27|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the 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:
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".
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.
The tree shows the occurrence of this domain across different species. More...
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.
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
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.
There are 10 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 SET domain has been found. There are 273 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 seqence.
Loading structure mapping...