Summary: SET domain
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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 histone lysine methyltransferases (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,
- Helin K, Dhanak D (October 2013). "Chromatin proteins and modifications as drug targets". Nature. 502 (7472): 480–8. doi:10.1038/nature12751. PMID 24153301.
- 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". Nature Genetics. 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". Current Biology. 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 Research. 29 (21): 4319–33. doi:10.1093/nar/29.21.4319. PMC . PMID 11691919.
- Kouzarides T (April 2002). "Histone methylation in transcriptional control". Current Opinion in Genetics & Development. 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". Molecular 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". Nature Structural Biology. 9 (11): 828–32. doi:10.1038/nsb860. PMID 12389037.
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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:||AWS PHD Pre-SET preSET_CXC 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:
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Author:||Bateman A , Huang S|
|Number in seed:||257|
|Number in full:||29913|
|Average length of the domain:||160.20 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||20.92 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||28|
|Download:||download the raw HMM for this family|
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The tree shows the occurrence of this domain across different species. More...
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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.
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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 344 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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