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153  structures 879  species 4  interactions 8450  sequences 382  architectures

Family: SET (PF00856)

Summary: SET domain

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This is the Wikipedia entry entitled "SET domain". More...

SET domain Edit Wikipedia article

SET
PDB 1n3j EBI.jpg
structure and substrate of a histone h3 lysine methyltransferase from paramecium bursaria chlorella virus 1
Identifiers
Symbol SET
Pfam PF00856
InterPro IPR001214
SMART SM0468
SCOP 1ml9
SUPERFAMILY 1ml9

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.

The SET domain appears generally as one part of a larger multidomain protein, and recently there were described three structures of very different proteins with distinct domain compositions: 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 and 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.[1] 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,[2] the HMTases belong to SET family that can be classified according to the sequences surrounding the SET domain.[3][4] 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.[5]

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.[6] The structured post-SET region brings in the C-terminal residues that participate in S-adenosylmethine-binding and histone tail interactions. The three conserved cysteine residues are essential for HMTase activity, as replacement with serine abolishes HMTase activity.[7][8]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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 60187. PMID 11691919. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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 2713655. PMID 12887903. 
  7. ^ 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 2713760. PMID 12372305. 
  8. ^ 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. 

Examples[edit]

Human genes encoding proteins containing this domain include:

SUV420H1, SUV420H2,

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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 60187. PMID 11691919. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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 2713655. PMID 12887903. 
  7. ^ 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 2713760. PMID 12372305. 
  8. ^ 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 article incorporates text from the public domain Pfam and InterPro IPR001214

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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) [2]. 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 [3]. 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 [5].

Literature references

  1. 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

  2. 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

  3. 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

  4. Min J, Zhang X, Cheng X, Grewal SI, Xu RM; , Nat Struct Biol 2002;0:0-0.: Structure of the SET domain histone lysine methyltransferase Clr4. PUBMED:12389037 EPMC:12389037

  5. Marmorstein R; , Trends Biochem Sci 2003;28:59-62.: Structure of SET domain proteins: a new twist on histone methylation. PUBMED:12575990 EPMC:12575990


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001214

The SET domain appears generally as one part of a larger multidomain protein, and recently there were described three structures of very different proteins with distinct domain compositions: 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 and 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 [PUBMED:9537414]. 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 [PUBMED:12123582], the HMTases belong to SET family that can be classified according to the sequences surrounding the SET domain [PUBMED:11691919, PUBMED:11893494]. 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 [PUBMED:12540855].

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 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 [PUBMED:12887903]. The structured post-SET region brings in the C-terminal residues that participate in S-adenosylmethine-binding and histone tail interactions. The three conserved cysteine residues are essential for HMTase activity, as replacement with serine abolishes HMTase activity [PUBMED:12372305], [PUBMED:12389037].

Gene Ontology

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Domain organisation

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Alignments

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  Seed
(267)
Full
(8450)
Representative proteomes NCBI
(8290)
Meta
(1539)
RP15
(1814)
RP35
(2953)
RP55
(4471)
RP75
(5532)
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  Seed
(267)
Full
(8450)
Representative proteomes NCBI
(8290)
Meta
(1539)
RP15
(1814)
RP35
(2953)
RP55
(4471)
RP75
(5532)
Alignment:
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  Seed
(267)
Full
(8450)
Representative proteomes NCBI
(8290)
Meta
(1539)
RP15
(1814)
RP35
(2953)
RP55
(4471)
RP75
(5532)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped 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.

External links

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Curation and family details

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Curation View help on the curation process

Seed source: [1]
Previous IDs: none
Type: Family
Author: Bateman A, Huang S
Number in seed: 267
Number in full: 8450
Average length of the domain: 133.10 aa
Average identity of full alignment: 21 %
Average coverage of the sequence by the domain: 17.69 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.0 21.0
Trusted cut-off 21.0 21.0
Noise cut-off 20.9 20.9
Model length: 162
Family (HMM) version: 23
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Species distribution

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Interactions

There are 4 interactions for this family. More...

Rubis-subs-bind Pre-SET SET MORN

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 SET domain has been found. There are 153 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.

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