{PDOC50813}
{PS50813; GAF}
{BEGIN}
**********************
* GAF domain profile *
**********************

GAF  domains  are  ubiquitous  motifs present in one, two, or three degenerate
copies  in  cyclic  GMP  (cGMP)-regulated cyclic nucleotide phosphodiesterases
(PDEs),  certain  adenylyl  cyclases, the bacterial transcription factor FhlA,
and  hundreds  of other signaling and sensory proteins from all three kingdoms
of life.   GAF  domains  in  general  may  regulate  allosterically  catalytic
activities via   the  binding  of  ligands,  such  as  nucleotides  and  small
molecules. Given the diverse evolutionary and functional contexts within which
GAF domains are found, it has been proposed that not all these domains possess
identical  functions.  Hence,  the GAF domains of cGMP-regulated PDEs and some
adenylyl cyclases contain a (R/K)X(m)NKX(n)D motif implicated in cGMP binding,
whereas  the  GAF  domains  of  plant  and  cyanobacterial  phytochromes  (see
<PDOC00218>) contain a cysteine that mediates chromophore attachment [1,2].

Resolution  of  the  crystal  structure  of  Saccharomyces cerevisiae YKG9 GAF
domain has revealed that the GAF domain forms dimers and consists of a central
antiparallel  six-stranded  beta-sheet  and  two outer layer. One of the outer
layer  is  made of four alpha-helices whereas the opposite outer layer, called
the  'irregular' layer, is a mixture of loops and a short alpha-helix. Despite
a  lack  of  sequence homology to any previously determined structure, the GAF
domain  shows  structural  similarities  to  PAS domains (see <PDOC50112>) and
profilin  (see  <PDOC00372>).  The  GAF  fold is a hybrid between the profilin
fold,  manifested  in  the  helical  and  central  layers,  and  the PAS fold,
manifested in the central and irregular layers [2].

Some proteins known to contain a GAF domain are listed below:

 - Vertebrate and invertebrate cGMP-stimulated PDEs.
 - Plant  and  cyanobacterial  phytochromes. Phytochromes are a major class of
   signal transducing photoreceptors in plants.
 - Plant ETR1, an ethylene receptor which is similar in domain architecture to
   phytochromes.
 - Bacterial  FhlA,  required  for  induction  of  expression  of  the formate
   dehydrogenase h and hydrogenase-3 structural genes.
 - Bacterial  nifA, a transcriptional activator, is required for activation of
   most nif  operons,  which  are directly involved in nitrogen fixation. nifA
   interacts with sigma-54.
 - Cyanobacterial adenylate cyclases (EC 4.6.1.1).
 - Mycobacterial  oxygen  sensor histidine kinase response regulator DevS/DosS
   that contains two GAF domains, the first of which binds heme [3].
 - Mycobacterial  MimR,  the  positive  regulator  of the mimABCD gene cluster
   expression that is responsive to acetone and related compounds [4].
 - Bacterial KdpD, a membrane bound potassium biosensor [5].
 - Agrobacterial VirA, an integral membrane histidine autokinase [6].
 - Mammalian  EF-hand  calcium-binding  domain-containing  protein  5 (EFCAB5)
   [7].

The profile we developed covers the entire GAF domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: February 2026 / First entry.

[ 1] Aravind L., Ponting C.P.
     "The GAF domain: an evolutionary link between diverse phototransducing
     proteins."
     Trends. Biochem. Sci. 22:458-459(1997).
     PubMed=9433123; DOI=10.1016/s0968-0004(97)01148-1
[ 2] Ho Y.-S.J., Burden L.M., Hurley J.H.
     "Structure of the GAF domain, a ubiquitous signaling motif and a new
     class of  cyclic GMP receptor."
     EMBO. J. 19:5288-5299(2000).
     PubMed=11032796; DOI=10.1093/emboj/19.20.5288
[ 3] Sardiwal S., Kendall S.L., Movahedzadeh F., Rison S.C.G., Stoker N.G.,
     Djordjevic S.
     "A GAF domain in the hypoxia/NO-inducible Mycobacterium tuberculosis
     DosS protein  binds haem."
     J. Mol. Biol. 353:929-936(2005).
     PubMed=16213520; DOI=10.1016/j.jmb.2005.09.011
[ 4] Furuya T., Hirose S., Semba H., Kino K.
     "Identification of the regulator gene responsible for the
     acetone-responsive  expression of the binuclear iron monooxygenase
     gene cluster in mycobacteria."
     J. Bacteriol. 193:5817-5823(2011).
     PubMed=21856847; DOI=10.1128/JB.05525-11
[ 5] Kumar S., Gillilan R.E., Yernool D.A.
     "Structure and function of the juxtamembrane GAF domain of potassium
     biosensor  KdpD."
     Protein. Sci. 29:2009-2021(2020).
     PubMed=32713093; DOI=10.1002/pro.3920
[ 6] Lin Y.-H., Pierce B.D., Fang F., Wise A., Binns A.N., Lynn D.G.
     "Role of the VirA histidine autokinase of Agrobacterium tumefaciens in
     the initial  steps of pathogenesis."
     Front. Plant. Sci. 5:195-195(2014).
     PubMed=24860585; DOI=10.3389/fpls.2014.00195
[ 7] Sigrist C.J.A.
     Unpublished observations (1992).

--------------------------------------------------------------------------------
PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and
distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives
(CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html
--------------------------------------------------------------------------------

{END}