Summary: GAF domain
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GAF domain Edit Wikipedia article
3',5'-Cyclic Nucleotide Phosphodiesterase 2A, Containing the GAF A and GAF B Domains.
The GAF domain is a type of protein domain that is found in a wide range of proteins from all species. The GAF domain is named after some of the proteins it is found in: cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA. The first structure of a GAF domain solved by Ho and colleagues showed that this domain shared a similar fold with the PAS domain. In mammals, GAF domains are found in five members of the cyclic nucleotide phosphodiesterase superfamily: PDE2, PDE5, and PDE6 which bind cGMP to the GAF domain, PDE10 which binds cAMP, and PDE11 which binds both cGMP and cAMP.
Human proteins containing this domain include:
- Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WG, Beavo JA (October 2002). "The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding". Proceedings of the National Academy of Sciences of the United States of America. 99 (20): 13260–5. Bibcode:2002PNAS...9913260M. doi:10.1073/pnas.192374899. JSTOR 3073384. PMC . PMID 12271124.
- Aravind L, Ponting CP (December 1997). "The GAF domain: an evolutionary link between diverse phototransducing proteins". Trends in Biochemical Sciences. 22 (12): 458–9. doi:10.1016/S0968-0004(97)01148-1. PMID 9433123.
- Ho YS, Burden LM, Hurley JH (October 2000). "Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor". The EMBO Journal. 19 (20): 5288–99. doi:10.1093/emboj/19.20.5288. PMC . PMID 11032796.
- Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S, Hetman J, Beavo JA, Phillips SC (March 2000). "Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3702–7. Bibcode:2000PNAS...97.3702F. doi:10.1073/pnas.050585197. JSTOR 121956. PMC . PMID 10725373.
- Schultz JE (2009). "Structural and biochemical aspects of tandem GAF domains". Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology. 191 (191): 93–109. doi:10.1007/978-3-540-68964-5_6. ISBN 978-3-540-68960-7. PMID 19089327.
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This domain is present in cGMP-specific phosphodiesterases, adenylyl and guanylyl cyclases, phytochromes, FhlA and NifA. Adenylyl and guanylyl cyclases catalyse ATP and GTP to the second messengers cAMP and cGMP, respectively, these products up-regulating catalytic activity by binding to the regulatory GAF domain(s). The opposite hydrolysis reaction is catalysed by phosphodiesterase. cGMP-dependent 3',5'-cyclic phosphodiesterase catalyses the conversion of guanosine 3',5'-cyclic phosphate to guanosine 5'-phosphate. Here too, cGMP regulates catalytic activity by GAF-domain binding. Phytochromes are regulatory photoreceptors in plants and bacteria which exist in two thermally-stable states that are reversibly inter-convertible by light: the Pr state absorbs maximally in the red region of the spectrum, while the Pfr state absorbs maximally in the far-red region. This domain is also found in FhlA (formate hydrogen lyase transcriptional activator) and NifA, a transcriptional activator which is required for activation of most Nif operons which are directly involved in nitrogen fixation. NifA interacts with sigma-54. This domain can bind biliverdine and phycocyanobilin (Matilla et al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
Santero E, Hoover TR, North AK, Berger DK, Porter SC, Kustu S;, J Mol Biol. 1992;227:602-620.: Role of integration host factor in stimulating transcription from the sigma 54-dependent nifH promoter. PUBMED:1404379 EPMC:1404379
Internal database links
|SCOOP:||Autoind_bind bHLH-MYC_N DUF3369 DUF484 GAF_2 GAF_3 IclR PAS_4 SpoVT_C|
|Similarity to PfamA using HHSearch:||GAF_2 GAF_3 SpoVT_C|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR003018
The GAF domain is named after some of the proteins it is found in, including cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA. It is also found in and guanylyl cyclases and phytochromes [ PUBMED:9433123 , PUBMED:20004158 ]. The structure of a GAF domain shows that the domain shares a similar fold with the PAS domain [ PUBMED:11032796 ]. Adenylyl and guanylyl cyclases catalyse ATP and GTP to the second messengers cAMP and cGMP respectively, these products up-regulating catalytic activity by binding to the regulatory GAF domain(s). The opposite hydrolysis reaction is catalysed by phosphodiesterase. cGMP-dependent 3',5'-cyclic phosphodiesterase catalyses the conversion of guanosine 3',5'-cyclic phosphate to guanosine 5'-phosphate. Here too, cGMP regulates catalytic activity by GAF-domain binding. Phytochromes are regulatory photoreceptors in plants and bacteria which exist in two thermally stable states that are reversibly inter-convertible by light, the Pr state absorbs maximally in the red region of the spectrum, while the Pfr state absorbs maximally in the far-red region [ PUBMED:20298248 ].
The GAF domain is also found in FhlA (formate hydrogen lyase transcriptional activator) and NifA, a transcriptional activator required for activation of most Nif operons, which are directly involved in nitrogen fixation. NifA interacts with sigma-54 [ PUBMED:1404379 ].
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
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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.
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A clan of related transcriptional regulator domains.
The clan contains the following 18 members:Autoind_bind bHLH-MYC_N CCB2_CCB4 CodY DraK_HK_N DUF3369 DUF484 DUF5628 GAF GAF_2 GAF_3 HbpS-like HNOBA HrcA IclR PdtaS_GAF PHY SpoVT_C
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 and the UniProtKB 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:
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- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
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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.
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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:||SMART, Hughes J|
|Number in seed:||442|
|Number in full:||40137|
|Average length of the domain:||146.90 aa|
|Average identity of full alignment:||14 %|
|Average coverage of the sequence by the domain:||22.22 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||29|
|Download:||download the raw HMM for this family|
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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:
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- highlight species that are represented in the seed alignment
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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.
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 GAF domain has been found. There are 298 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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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.