Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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GAF Domain present in phytochromes and cGMP-specific phosphodiesterases.

SMART accession number:	SM00065
Description:	Mutations within these domains in PDE6B result in autosomal recessive inheritance of retinitis pigmentosa.
Interpro abstract (IPR003018):	The GAF domain is present in cGMP-specific phosphodiesterases, adenylyl and guanylyl cyclases and phytochromes [(PUBMED:9433123), (PUBMED:20004158)]. 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)].
GO function:	protein binding (GO:0005515)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 16092 GAF domains in 14178 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a GAF domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with GAF domain is also avaliable.

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  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: chromophore-binding

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Aravind L, Ponting CP
  • The GAF domain: an evolutionary link between diverse phototransducing proteins.
  • Trends Biochem Sci. 1997; 22: 458-9

  • McAllister-Lucas LM et al.
  • An essential aspartic acid at each of two allosteric cGMP-binding sites of a cGMP-specific phosphodiesterase.
  • J Biol Chem. 1995; 270: 30671-9
  • Display abstract

  • The amino acid sequences of all known cGMP-binding phosphodiesterases (PDEs) contain internally homologous repeats (a and b) that are 80-90 residues in length and are arranged in tandem within the putative cGMP-binding domains. In the bovine lung cGMP-binding, cGMP-specific PDE (cGB-PDE or PDE5A), these repeats span residues 228-311 (a) and 410-500 (b). An aspartic acid (residue 289 or 478) that is invariant in repeats a and b of all known cGMP-binding PDEs was changed to alanine by site-directed mutagenesis of cGB-PDE, and wild type (WT) and mutant cGB-PDEs were expressed in COS-7 cells. Purified bovine lung cGB-PDE (native) and WT cGB-PDE displayed identical cGMP-binding kinetics, with approximately 1.8 microM cGMP required for half-maximal saturation. The D289A mutant showed decreased affinity for cGMP (Kd > 10 microM) and the D478A mutant showed increased affinity for cGMP (Kd approximately 0.5 microM) as compared to WT and native cGB-PDE. WT and native cGB-PDE displayed an identical curvilinear profile of cGMP dissociation which was consistent with the presence of distinct slowly dissociating (koff = 0.26 h-1) and rapidly dissociating (koff = 1.00 h-1) sites of cGMP binding. In contrast, the D289A mutant displayed a single koff = 1.24 h-1, which was similar to the calculated koff for the fast site of WT and native cGB-PDE, and the D478A mutant displayed a single koff = 0.29 h-1, which was similar to that calculated for the slow site of WT and native cGB-PDE. These results were consistent with the loss of a slow cGMP-binding site in repeat a of the D289A mutant cGB-PDE, and the loss of a fast site in repeat b of the D478A mutant, suggesting that cGB-PDE possesses two distinct cGMP-binding sites located at repeats a and b, with the invariant aspartic acid being crucial for interaction with cGMP at each site.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the GAF domain.

  Protein	Disease
  Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta (P35913) (SMART)	OMIM:180072: Night blindness, congenital stationary, type 3 OMIM:163500: Retinitis pigmentosa, autosomal recessive
  Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha (P16499) (SMART)	OMIM:180071: Retinitis pigmentosa, autosomal recessive

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 43.91 map02020 Two-component system - General 21.07 map02060 Phosphotransferase system (PTS) 11.17 map00230 Purine metabolism 9.39 map00910 Nitrogen metabolism 6.85 map04914 Progesterone-mediated oocyte maturation 1.78 map02030 Bacterial chemotaxis - General 1.78 map03090 Type II secretion system 0.51 map00562 Inositol phosphate metabolism 0.51 map00632 Benzoate degradation via CoA ligation 0.25 map00260 Glycine, serine and threonine metabolism 0.25 map00280 Valine, leucine and isoleucine degradation 0.25 map00760 Nicotinate and nicotinamide metabolism 0.25 map04510 Focal adhesion 0.25 map03320 PPAR signaling pathway 0.25 map00071 Fatty acid metabolism 0.25 map04810 Regulation of actin cytoskeleton 0.25 map00410 beta-Alanine metabolism 0.25 map04020 Calcium signaling pathway 0.25 map00640 Propanoate metabolism 0.25 map03060 Protein export 0.25 map00540 Lipopolysaccharide biosynthesis This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with GAF domain which could be assigned to a KEGG orthologous group, and not all proteins containing GAF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of GAF domains in PDB

  PDB code	Main view	Title
  1f5m		Structure of the gaf domain
  1mc0		Regulatory segment of mouse 3',5'-cyclic nucleotide phosphodiesterase 2a, containing the gaf a and gaf b domains
  1vhm		Crystal structure of an hypothetical protein
  1ykd		Crystal structure of the tandem gaf domains from a cyanobacterial adenylyl cyclase: novel modes of ligand- binding and dimerization
  1ztu		Structure of the chromophore binding domain of bacterial phytochrome
  2k2n		Solution structure of a cyanobacterial phytochrome gaf domain in the red light-absorbing ground state
  2k31		Solution structure of cgmp-binding gaf domain of phosphodiesterase 5
  2kli		Structural basis for the photoconversion of a phytochrome to the activated far-red light-absorbing form
  2koi		Refined solution structure of a cyanobacterial phytochrome gaf domain in the red light-absorbing ground state
  2o9b		Crystal structure of bacteriophytochrome chromophore binding domain
  2o9c		Crystal structure of bacteriophytochrome chromophore binding domain at 1.45 angstrom resolution
  2ool		Crystal structure of the chromophore-binding domain of an unusual bacteriophytochrome rpbphp3 from r. palustris
  2qyb		Crystal structure of the gaf domain region of putative membrane protein from geobacter sulfurreducens pca
  2vea		The complete sensory module of the cyanobacterial phytochrome cph1 in the pr-state.
  2vjw		Crystal structure of the second gaf domain of devs from mycobacterium smegmatis
  2vks		Crystal structure of gaf-b domain of devs from mycobacterium smegmatis
  2vzw		X-ray structure of the heme-bound gaf domain of sensory histidine kinase dost of mycobacterium tuberculosis
  2w3d		Structure of the first gaf domain of mycobacterium tuberculosis doss
  2w3e		Oxidized structure of the first gaf domain of mycobacterium tuberculosis doss
  2w3f		Reduced structure of the first gaf domain of mycobacterium tuberculosis doss
  2w3g		Air-oxidized structure of the first gaf domain of mycobacterium tuberculosis doss
  2w3h		Cyanide bound structure of the first gaf domain of mycobacterium tuberculosis doss
  2zmf		Crystal structure of the c-terminal gaf domain of human phosphodiesterase 10a
  3bjc		Crystal structure of the pde5a catalytic domain in complex with a novel inhibitor
  3c2w		Crystal structure of the photosensory core domain of p. aeruginosa bacteriophytochrome pabphp in the pfr state
  3ci6		Crystal structure of the gaf domain from acinetobacter phosphoenolpyruvate-protein phosphotransferase
  3cit		Crystal structure of the gaf domain of a putative sensor histidine kinase from pseudomonas syringae pv. tomato
  3dba		Crystal structure of the cgmp-bound gaf a domain from the photoreceptor phosphodiesterase 6c
  3e0y		The crystal structure of a conserved domain from a protein of geobacter sulfurreducens pca
  3eea		The crystal structure of the gaf domain/hd domain protein from geobacter sulfurreducens
  3g6o		Crystal structure of p. aeruginosa bacteriophytochrome pabphp photosensory core domain mutant q188l
  3hcy		The crystal structure of the domain of putative two- component sensor histidine kinase protein from sinorhizobium meliloti 1021
  3ibj		X-ray structure of pde2a
  3ibr		Crystal structure of p. aeruginosa bacteriophytochrome photosensory core module mutant q188l in the mixed pr/pfr state

• Links (links to other resources describing this domain)

• INTERPRO	IPR003018

Send comments to Ivica Letunic