{PDOC00522}
{PS00601; IRF_1}
{PS51507; IRF_2}
{BEGIN}
*************************************************************************
* IRF tryptophan pentad repeat DNA-binding domain signature and profile *
*************************************************************************

Viral infections induce  the  expression  of type I interferons (IFN-alpha and
IFN-beta) genes. The induction is due to the transcriptional activation of the
IFN genes.  Interferon regulatory factor I (IRF-1) is one of the transcription
factors responsible for that activation. IRF-1 binds to an upstream regulatory
cis element, known as the interferon consensus sequence (ICS),  which is found
in the promoters of type I IFN and IFN-inducible MHC class I genes. Interferon
regulatory factor 2 (IRF-2) is a protein that also interacts with the ICS, but
that does not function as an activator;  rather, it suppresses the function of
IRF-1 under certain circumstances [1].

These proteins  share  a highly conserved N-terminal domain of about 100 amino
acid residues  which  is  involved  in  DNA-binding  and  which  contain  five
conserved tryptophan. This domain is known as a 'tryptophan pentad repeat' or
a 'tryptophan cluster' and is also present in:

 - Interferon consensus sequence binding protein (ICSBP) [2],  a transcription
   factor expressed predominantly in lymphoid tissues and induced by IFN-gamma
   that also binds to the ICS.
 - Transcriptional regulator ISGF3 gamma subunit [3]. ISGF3 is responsible for
   the initial stimulation of interferon-alpha-responsive genes. It recognizes
   and binds to  the interferon-stimulated  response element (ISRE) within the
   regulatory sequences of target genes.
 - Interferon regulatory factor 3 (IRF-3).
 - Interferon  regulatory  factor  4  (IRF-4)  which  binds to the interferon-
   stimulated response element (ISRE) of the MHC class I promoter.
 - Interferon regulatory factor 5 (IRF-5).
 - Interferon regulatory factor 6 (IRF-6).
 - Interferon regulatory factor 7 (IRF-7).
 - Gamma  Herpesviruses  vIRF-1,  -2  and  -3,  proteins  with homology to the
   cellular transcription  factors  of  the IRF family [4]. Neither vIRF-1 nor
   vIRF-2 bind  to  DNA with the same specificity as cellular IRFs, indicating
   that if  vIRFs  are  DNA-binding  proteins,  their  binding  has  a pattern
   distinct from  that  of the cellular IRFs. Whether vIRF-3 can bind DNA with
   the same specificity as cellular IRFs is not known.

The IRF   tryptophan  pentad  repeat  DNA-binding  domain  has  an  alpha/beta
architecture comprising  a  cluster  of  three  alpha-helices  (alpha1-alpha3)
flanked on  one  side  by  a mixed four-stranded beta-sheet (beta1-beta4) (see
<PDB:1IF1>). It  forms  a  helix-turn-helix motif that binds to ISRE consensus
sequences found  in target promoters. Three of the tryptophan residues contact
DNA by recognizing a GAAA sequence [5].

As a  signature  for  this  domain, we selected the region that spans from the
second to  the  fourth  of the five conserved tryptophans. We also developed a
profile which  covers  the  entire  IRF  tryptophan  pentad repeat DNA-binding
domain.

-Consensus pattern: W-x-[DNH]-x(5)-[LIVF]-x-[IV]-P-W-x-H-x(9,10)-[DE]-x(2)-
                    [LIVF]-F-[KRQ]-x-[WR]-A
-Sequences known to belong to this class detected by the pattern: ALL,  except
 bovine IRF-3.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: August 2010 / Text revised; profile added.

[ 1] Taniguchi T.
     "Regulation of interferon-beta gene: structure and function of
     cis-elements and trans-acting factors."
     J. Interferon Res. 9:633-640(1989).
     PubMed=2691585
[ 2] Driggers P.H., Ennist D.L., Gleason S.L., Mak W.-H., Marks M.S.,
     Levi B.-Z., Flanagan J.R., Appella E., Ozato K.
     "An interferon gamma-regulated protein that binds the
     interferon-inducible enhancer element of major histocompatibility
     complex class I genes."
     Proc. Natl. Acad. Sci. U.S.A. 87:3743-3747(1990).
     PubMed=2111015
[ 3] Veals S.A., Schindler C., Leonard D., Fu X.-Y., Aebersold R.,
     Darnell J.E. Jr., Levy D.E.
     "Subunit of an alpha-interferon-responsive transcription factor is
     related to interferon regulatory factor and Myb families of
     DNA-binding proteins."
     Mol. Cell. Biol. 12:3315-3324(1992).
     PubMed=1630447
[ 4] Lubyova B., Pitha P.M.
     "Characterization of a novel human herpesvirus 8-encoded protein,
     vIRF-3, that shows homology to viral and cellular interferon
     regulatory factors."
     J. Virol. 74:8194-8201(2000).
     PubMed=10933732
[ 5] Escalante C.R., Yie J., Thanos D., Aggarwal A.K.
     "Structure of IRF-1 with bound DNA reveals determinants of interferon
     regulation."
     Nature 391:103-106(1998).
     PubMed=9422515; DOI=10.1038/34224

--------------------------------------------------------------------------------
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}