Summary

HhH-GPD superfamily base excision DNA repair protein

This family contains a diverse range of structurally related DNA repair proteins. The superfamily is called the HhH-GPD family after its hallmark Helix-hairpin-helix and Gly/Pro rich loop followed by a conserved aspartate [2]. This includes endonuclease III, EC:4.2.99.18 and MutY an A/G-specific adenine glycosylase, both have a C terminal 4Fe-4S cluster. The family also includes 8-oxoguanine DNA glycosylases such as P53397. The methyl-CPG binding protein MBD4 Q9Z2D7 also contains a related domain [1] that is a thymine DNA glycosylase. The family also includes DNA-3-methyladenine glycosylase II EC:3.2.2.21 and other members of the AlkA family.

Literature references

Hendrich B, Hardeland U, Ng HH, Jiricny J, Bird A; , Nature 1999;401:301-304.: The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. PUBMED:10499592
Bruner SD, Norman DP, Verdine GL; , Nature 2000;403:859-866.: Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. PUBMED:10706276

InterPro entry IPR003265

Endonuclease III () is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism PUBMED:7773744, PUBMED:9032058. The structurally related DNA glycosylase MutY recognises and excises the mutational intermediate 8-oxoguanine-adenine mispair PUBMED:1328155. The 3-D structures of Escherichia coli endonuclease III PUBMED:1411536 and catalytic domain of MutY PUBMED:9846876 have been determined. The structures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key, four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with the [Fe4S4] cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation pattern Cys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif is referred to as a [Fe4S4] cluster loop (FCL) PUBMED:7664751. Two DNA-binding motifs have been proposed, one at either end of the interdomain groove: the helix-hairpin-helix (HhH) and FCL motifs (see ). The primary role of the iron-sulphur cluster appears to involve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop of the FCL motif PUBMED:7664751, PUBMED:10900127.

The HhH-GPD domain gets its name from its hallmark helix-hairpin-helix and Gly/Pro rich loop followed by a conserved aspartate. This domain is found in a diverse range of structurally related DNA repair proteins that include: endonuclease III, and DNA glycosylase MutY, an A/G-specific adenine glycosylase. Both of these enzymes have a C-terminal iron-sulphur cluster loop (FCL). The methyl-CPG binding protein (MBD4) also contain a related domain that is a thymine DNA glycosylase. The family also includes DNA-3-methyladenine glycosylase II , 8-oxoguanine DNA glycosylases and other members of the AlkA family.

Clan

This family is a member of clan HHH (CL0198), which contains the following 7 members:

Cdd1 GspK HHH HhH-GPD IMS_HHH TfoX_C Transposase_20

Gene Ontology

Biological process

base-excision repair (GO:0006284)

External database links

HOMSTRAD:	Endonuclease_3
PANDIT:	PF00730
PROSITE:	PDOC00615 PDOC00447
SCOP:	2abk
SYSTERS:	HhH-GPD

Domain organisation

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

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Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (72) Full (5287) NCBI (10573) Metagenomics (6181)
Viewer:

Formatting options

Alignment:	Seed (72) Full (5287)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

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

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (72) Full (5287) NCBI (10573) Metagenomics (6181)
Full length sequences	Full-sequences (5287)

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER2.

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. 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 or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

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:

Pfam-B_854 (release 2.1)

Previous IDs:

Endonuclease_3;

Type:

Domain

Author:

Bateman A

Number in seed:

72

Number in full:

5287

Average length of the domain:

138.00 aa

Average identity of full alignment:

22 %

Average coverage of the sequence by the domain:

47.56 %

HMM information

HMM build commands:

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

search method: hmmsearch -Z 9421015 -E 1000 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	21.9	21.9
Trusted cut-off	21.9	22.0
Noise cut-off	21.7	21.8

Model length:

121

Family (HMM) version:

18

Download:

download the raw HMM for this family

Species distribution

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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Interactions

There are 5 interactions for this family. More...

EndIII_4Fe-2S AlkA_N OGG_N HhH-GPD HHH

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 MSD 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 HhH-GPD domain has been found.

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Family: HhH-GPD (PF00730)

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