The domain within your query sequence starts at position 101 and ends at position 254; the E-value for the GAF domain shown below is 1.44e-3.

DNHLLLYELSSIIRIATKADGFALYFLGECNNSLCVFIPPGMKEGQPRLIPAGPITQGTT
ISAYVAKSRKTLLVEDILGDERFPRGTGLESGTRIQSVLCLPIVTAIGDLIGILELYRHW
GKEAFCLSHQEVATANLAWASVAIHQVQVCRGLA

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 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) ].

• GO function: protein binding (GO:0005515)

There are 232204 GAF domains in 203968 proteins in SMART's nrdb database.

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

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)

% 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	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
2lb5	Refined Structural Basis for the Photoconversion of A Phytochrome to the Activated FAR-RED LIGHT-ABSORBING Form
2lb9	Refined solution structure of a cyanobacterial phytochrome gaf domain in the red light-absorbing ground state (corrected pyrrole ring planarity)
2m7u	Blue Light-Absorbing State of TePixJ, an Active Cyanobacteriochrome Domain
2m7v	Green Light-Absorbing State of TePixJ, an Active Cyanobacteriochrome Domain
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
2xss	Crystal structure of GAFb from the human phosphodiesterase 5
2y79	STRUCTURE OF THE FIRST GAF DOMAIN E87A MUTANT OF MYCOBACTERIUM TUBERCULOSIS DOSS
2y8h	STRUCTURE OF THE FIRST GAF DOMAIN E87G MUTANT 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
3jab	3JAB
3jbq	3JBQ
3k2n	The crystal structure of sigma-54-dependent transcriptional regulator domain from Chlorobium Tepidum TLS
3ko6	Crystal structure of yeast free methionine-R-sulfoxide reductase Ykg9 in complex with the substrate
3ksf	structure of fRMsr of Staphylococcus aureus (reduced form)
3ksg	structure of fRMsr of Staphylococcus aureus (complex with substrate)
3ksh	Structure of fRMsr of Staphylococcus aureus (oxidized form)
3ksi	structure of fRMsr of Staphylococcus aureus (complex with 2-propanol)
3lfv	crystal structure of unliganded PDE5A GAF domain
3mf0	Crystal structure of PDE5A GAF domain (89-518)
3mmh	X-ray structure of free methionine-R-sulfoxide reductase from neisseria meningitidis in complex with its substrate
3nhq	The dark Pfr structure of the photosensory core module of P. aeruginosa Bacteriophytochrome
3nop	Light-induced intermediate structure L1 of Pseudomonas aeruginosa bacteriophytochrome
3not	Light-induced intermediate structure L2 of P. aeruginosa bacteriophytochrome
3nou	Light-induced intermediate structure L3 of P. aeruginosa bacteriophytochrome
3o5y	The Crystal Structure of the GAF domain of a two-component sensor histidine kinase from Bacillus halodurans to 2.45A
3oov	Crystal structure of a methyl-accepting chemotaxis protein, residues 122 to 287
3p01	Crystal structure of two-component response regulator from Nostoc sp. PCC 7120
3rfb	Structure of fRMsr
3s7n	Crystal Structure of the alternate His 207 conformation of the Infrared Fluorescent D207H variant of Deinococcus Bacteriophytochrome chromophore binding domain at 2.45 angstrom resolution
3s7o	Crystal Structure of the Infrared Fluorescent D207H variant of Deinococcus Bacteriophytochrome chromophore binding domain at 1.24 angstrom resolution
3s7p	Crystal Structure of the Infrared Fluorescent D207H variant of Deinococcus Bacteriophytochrome chromophore binding domain at 1.72 angstrom resolution
3s7q	Crystal Structure of a Monomeric Infrared Fluorescent Deinococcus radiodurans Bacteriophytochrome chromophore binding domain
3trc	Structure of the GAF domain from a phosphoenolpyruvate-protein phosphotransferase (ptsP) from Coxiella burnetii
3vv4	Crystal structure of cyanobacteriochrome TePixJ GAF domain
3w2z	Crystal structure of the cyanobacterial protein
3zq5	Structure of the Y263F mutant of the cyanobacterial phytochrome Cph1
4bwi	Structure of the phytochrome Cph2 from Synechocystis sp. PCC6803
4cqh	4CQH
4dmz	PelD 156-455 from Pseudomonas aeruginosa PA14, apo form
4dn0	PelD 156-455 from Pseudomonas aeruginosa PA14 in complex with c-di-GMP
4e04	RpBphP2 chromophore-binding domain crystallized by homologue-directed mutagenesis.
4etx	Crystal Structure of PelD 158-CT from Pseudomonas aeruginosa PAO1
4etz	Crystal Structure of PelD 158-CT from Pseudomonas aeruginosa PAO1
4eu0	Crystal Structure of PelD 158-CT from Pseudomonas aeruginosa PAO1
4euv	Crystal Structure of PelD 158-CT from Pseudomonas aeruginosa PAO1, in complex with c-di-GMP, form 1
4fof	Crystal Structure of the blue-light absorbing form of the Thermosynechococcus elongatus PixJ GAF-domain
4g3k	Crystal structure of a. aeolicus nlh1 gaf domain in an inactive state
4g3v	Crystal structure of A. Aeolicus nlh2 gaf domain in an inactive state
4g3w	Crystal structure of a. aeolicus nlh1 gaf domain in an inactive state
4glq	Crystal Structure of the blue-light absorbing form of the Thermosynechococcus elongatus PixJ GAF-domain
4gw9	Structure of a bacteriophytochrome and light-stimulated protomer swapping with a gene repressor
4ijg	Crystal structure of monomeric bacteriophytochrome
4lrx	Crystal Structure of the E.coli DhaR(N)-DhaK complex
4lry	Crystal Structure of the E.coli DhaR(N)-DhaK(T79L) complex
4lrz	Crystal Structure of the E.coli DhaR(N)-DhaL complex
4mcw	Metallo-enzyme from P. marina
4mdz	Metallo-enzyme from P. marina
4me4	Metallo-enzyme from P. marina
4mmn	4MMN
4mn7	4MN7
4o01	Crystal Structure of D. radiodurans Bacteriophytochrome Photosensory Core Module in its Illuminated Form
4o0p	Crystal Structure of D. radiodurans Bacteriophytochrome Photosensory Core Module in its Dark Form
4o8g	4O8G
4our	4OUR
4pau	4PAU
4q0h	4Q0H
4q0i	4Q0I
4q0j	4Q0J
4r6l	4R6L
4r70	4R70
4rpw	4RPW
4rq9	4RQ9
4s21	4S21
4xtq	4XTQ
4y3i	4Y3I
4y5f	4Y5F
4ynr	4YNR
4yof	4YOF
4z1w	4Z1W
4zmu	4ZMU
4zrr	4ZRR
5ajg	5AJG
5akp	5AKP
5c5k	5C5K
5dfx	5DFX
5dfy	5DFY
5hl6	5HL6
5hsq	5HSQ
5i5l	5I5L
5k5b	5K5B
5l8m	5L8M
5lbr	5LBR

Links (links to other resources describing this domain)

• INTERPRO: IPR003018