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70  structures 3675  species 4  interactions 5357  sequences 25  architectures

Family: H2TH (PF06831)

Summary: Formamidopyrimidine-DNA glycosylase H2TH domain

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H2TH domain Edit Wikipedia article

H2TH
PDB 1tdz EBI.jpg
crystal structure complex between the lactococcus lactis fpg (mutm) and a fapy-dg containing dna
Identifiers
Symbol H2TH
Pfam PF06831
Pfam clan CL0303
InterPro IPR015886
PROSITE PDOC00956
SCOP 1k82
SUPERFAMILY 1k82

In molecular biology, the H2TH domain (helix-2turn-helix domain) is a DNA-binding domain found in DNA glycosylase/AP lyase enzymes, which are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Most damage to bases in DNA is repaired by the base excision repair pathway.[1] These enzymes are primarily from bacteria, and have both DNA glycosylase activity EC 3.2.2.- and AP lyase activity EC 4.2.99.18. Examples include formamidopyrimidine-DNA glycosylases (Fpg; MutM) and endonuclease VIII (Nei).

Formamidopyrimidine-DNA glycosylases (Fpg, MutM) is a trifunctional DNA base excision repair enzyme that removes a wide range of oxidation-damaged bases (N-glycosylase activity; EC 3.2.2.23) and cleaves both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity;EC 4.2.99.18). Fpg has a preference for oxidised purines, excising oxidised purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). Its AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge.[2] The two DNA-binding motifs (a zinc finger and the H2TH (helix-two-turns-helix) motifs) suggest that the oxidised base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes.[2] Fpg binds one ion of zinc at the C terminus, which contains four conserved and essential cysteines.[3][4]

Endonuclease VIII (Nei) has the same enzyme activities as Fpg above (EC 3.2.2.-,EC 4.2.99.18), but with a preference for oxidized pyrimidines, such as thymine glycol, 5,6-dihydrouracil and 5,6-dihydrothymine.[5] These proteins contain three structural domains: an N-terminal catalytic core domain, a central helix-two turn-helix (H2TH) module and a C-terminal zinc finger (see PDB:1K82).[6] The N-terminal catalytic domain and the C-terminal zinc finger straddle the DNA with the long axis of the protein oriented roughly orthogonal to the helical axis of the DNA. Residues that contact DNA are located in the catalytic domain and in a beta-hairpin loop formed by the zinc finger.[7]

References

  1. ^ Fromme JC, Verdine GL (2004). "Base excision repair". Adv. Protein Chem. 69: 1–41. doi:10.1016/S0065-3233(04)69001-2. PMID 15588838. 
  2. ^ a b Sugahara M, Mikawa T, Kumasaka T, Yamamoto M, Kato R, Fukuyama K, Inoue Y, Kuramitsu S (August 2000). "Crystal structure of a repair enzyme of oxidatively damaged DNA, MutM (Fpg), from an extreme thermophile, Thermus thermophilus HB8". EMBO J. 19 (15): 3857–69. doi:10.1093/emboj/19.15.3857. PMC 306600. PMID 10921868. 
  3. ^ O'Connor TR, Graves RJ, de Murcia G, Castaing B, Laval J (April 1993). "Fpg protein of Escherichia coli is a zinc finger protein whose cysteine residues have a structural and/or functional role". J. Biol. Chem. 268 (12): 9063–70. PMID 8473347. 
  4. ^ Duwat P, de Oliveira R, Ehrlich SD, Boiteux S (February 1995). "Repair of oxidative DNA damage in gram-positive bacteria: the Lactococcus lactis Fpg protein". Microbiology (Reading, Engl.) 141 (2): 411–7. doi:10.1099/13500872-141-2-411. PMID 7704272. 
  5. ^ Doublie S, Bandaru V, Bond JP, Wallace SS (July 2004). "The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity". Proc. Natl. Acad. Sci. U.S.A. 101 (28): 10284–9. doi:10.1073/pnas.0402051101. PMC 478564. PMID 15232006. 
  6. ^ Gilboa R, Zharkov DO, Golan G, Fernandes AS, Gerchman SE, Matz E, Kycia JH, Grollman AP, Shoham G (May 2002). "Structure of formamidopyrimidine-DNA glycosylase covalently complexed to DNA". J. Biol. Chem. 277 (22): 19811–6. doi:10.1074/jbc.M202058200. PMID 11912217. 
  7. ^ Fromme JC, Verdine GL (July 2002). "Structural insights into lesion recognition and repair by the bacterial 8-oxoguanine DNA glycosylase MutM". Nat. Struct. Biol. 9 (7): 544–52. doi:10.1038/nsb809. PMID 12055620. 

This article incorporates text from the public domain Pfam and InterPro IPR015886

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Formamidopyrimidine-DNA glycosylase H2TH domain Provide feedback

Formamidopyrimidine-DNA glycosylase (Fpg) is a DNA repair enzyme that excises oxidised purines from damaged DNA. This family is the central domain containing the DNA-binding helix-two turn-helix domain [1].

Literature references

  1. Gilboa R, Zharkov DO, Golan G, Fernandes AS, Gerchman SE, Matz E, Kycia JH, Grollman AP, Shoham G; , J Biol Chem 2002;277:19811-19816.: Structure of formamidopyrimidine-DNA glycosylase covalently complexed to DNA. PUBMED:11912217 EPMC:11912217


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR015886

This entry represents a helix-2turn-helix DNA-binding domain found in DNA glycosylase/AP lyase enzymes, which are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Most damage to bases in DNA is repaired by the base excision repair pathway [PUBMED:15588838]. These enzymes are primarily from bacteria, and have both DNA glycosylase activity (EC) and AP lyase activity (EC). Examples include formamidopyrimidine-DNA glycosylases (Fpg; MutM) and endonuclease VIII (Nei).

Formamidopyrimidine-DNA glycosylases (Fpg, MutM) is a trifunctional DNA base excision repair enzyme that removes a wide range of oxidation-damaged bases (N-glycosylase activity; EC) and cleaves both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity; EC). Fpg has a preference for oxidised purines, excising oxidized purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). ITs AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge [PUBMED:10921868]. The two DNA-binding motifs (a zinc finger and the helix-two-turns-helix motifs) suggest that the oxidized base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes [PUBMED:10921868]. Fpg binds one ion of zinc at the C terminus, which contains four conserved and essential cysteines [PUBMED:8473347, PUBMED:7704272].

Endonuclease VIII (Nei) has the same enzyme activities as Fpg above (EC, EC), but with a preference for oxidized pyrimidines, such as thymine glycol, 5,6-dihydrouracil and 5,6-dihydrothymine [PUBMED:15232006].

These protein contains three structural domains: an N-terminal catalytic core domain, a central helix-two turn-helix (H2TH) module and a C-terminal zinc finger [PUBMED:11912217]. The N-terminal catalytic domain and the C-terminal zinc finger straddle the DNA with the long axis of the protein oriented roughly orthogonal to the helical axis of the DNA. Residues that contact DNA are located in the catalytic domain and in a beta-hairpin loop formed by the zinc finger [PUBMED:12055620].

This entry represents the central domain containing the DNA-binding helix-two turn-helix domain [PUBMED:11912217].

Gene Ontology

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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 H2TH (CL0303), which has the following description:

This domain is thought to play a role in binding nucleic acids. It is DNA binding in nucleases and RNA-binding in ribosomal S13.

The clan contains the following 3 members:

FbpA H2TH Ribosomal_S13

Alignments

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  Seed
(19)
Full
(5357)
Representative proteomes NCBI
(3734)
Meta
(2235)
RP15
(400)
RP35
(799)
RP55
(1061)
RP75
(1277)
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Format an alignment

  Seed
(19)
Full
(5357)
Representative proteomes NCBI
(3734)
Meta
(2235)
RP15
(400)
RP35
(799)
RP55
(1061)
RP75
(1277)
Alignment:
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  Seed
(19)
Full
(5357)
Representative proteomes NCBI
(3734)
Meta
(2235)
RP15
(400)
RP35
(799)
RP55
(1061)
RP75
(1277)
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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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Trees

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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 View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 19
Number in full: 5357
Average length of the domain: 91.20 aa
Average identity of full alignment: 32 %
Average coverage of the sequence by the domain: 32.59 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.8 20.8
Trusted cut-off 20.8 20.8
Noise cut-off 20.6 20.7
Model length: 93
Family (HMM) version: 9
Download: download the raw HMM for this family

Species distribution

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Interactions

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

Fapy_DNA_glyco zf-FPG_IleRS Neil1-DNA_bind H2TH

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 H2TH domain has been found. There are 70 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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