{PDOC51771}
{PS51771; CGT_MARTX_CPD}
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* CGT/MARTX cysteine protease (CPD) domain profile *
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Large bacterial  protein toxins autotranslocate functional effector domains to
the eukaryotic  cell  cytosol,  resulting in alterations to cellular functions
that ultimately  benefit  the  infecting  pathogen.  Among  these  toxins, the
clostridial glucosylating toxins (CGTs) produced by Gram-positive bacteria and
the multifunctional-autoprocessing   RTX   (MARTX)   toxins  of  Gram-negative
bacteria have   distinct   mechanisms  of  post-translocation,  but  a  shared
mechanism of  post-translocation autoprocessing that releases these functional
domains from  the  large  holotoxins.  These toxins carry an embedded cysteine
protease domain  (CPD)  that  is  regulated  by a unique allosteric activation
mechanism. Binding   of   the   eukaryotic-specific  small  molecule  inositol
hexakisphosphate (InsP(6))   to  a  basic  cleft  within  the  CPD  induces  a
structural rearrangement   that  exposes  the  protease  active  site  to  its
substrates. The  CGT  and  MARTX  toxin CPDs form peptidase family C80 [E1] of
clan CD [1,2,3,4].

The CGT/MARTX  CPD  domain consists of a central beta-sheet that is surrounded
by alpha-helices.  Additional  beta-strands at the C-terminus form a subdomain
known as  the  beta-flap,  that  is loosely attached to the core protease (see
<PDB:3EEB>). The  CGT/MARTX  CPD catalytic dyad is composed of one His and one
Cys residue.  The  distance  between the catalytic residues indicates that the
Cys is not activated by protonation from His, but rather suggests that the Cys
is substrate-activated  by close alignment of the scissile bond, while the His
functions solely to protonate the leaving group [1,3,4].

Some proteins known to contain a CGT/MARTX CPD domain are listed below:

 - Clostridium difficile Toxin A (TcdA) and Toxin B (TcdB), the major
   virulence factors of clinically important antibiotic-associated diarrheal
   infections and pseudomembranous colitis.
 - Clostridium sordellii Lethal Toxin (TcsL).
 - Clostridium novyi alpha-toxin (TcnAlpha).
 - Vibrio cholerae MARTX.
 - Vibrio vulnificus MARTX.
 - Vibrio anguillarum MARTX.
 - Proteus MARTX.
 - Aeromonas MARTX.
 - Yersinia MARTX.
 - Photorhabdus MARTX.

The profile we developed covers the entire CGT/MARTX CPD domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: August 2015 / First entry.

[ 1] Egerer M., Satchell K.J.F.
     "Inositol hexakisphosphate-induced autoprocessing of large bacterial
     protein toxins."
     PLoS Pathog. 6:E1000942-E1000942(2010).
     PubMed=20628577; DOI=10.1371/journal.ppat.1000942
[ 2] Sheahan K.-L., Cordero C.L., Satchell K.J.F.
     "Autoprocessing of the Vibrio cholerae RTX toxin by the cysteine
     protease domain."
     EMBO J. 26:2552-2561(2007).
     PubMed=17464284; DOI=10.1038/sj.emboj.7601700
[ 3] Lupardus P.J., Shen A., Bogyo M., Garcia K.C.
     "Small molecule-induced allosteric activation of the Vibrio cholerae
     RTX cysteine  protease domain."
     Science 322:265-268(2008).
     PubMed=18845756; DOI=10.1126/science.1162403
[ 4] Shen A., Lupardus P.J., Albrow V.E., Guzzetta A., Powers J.C.,
     Garcia K.C., Bogyo M.
     "Mechanistic and structural insights into the proteolytic activation
     of Vibrio cholerae MARTX toxin."
     Nat. Chem. Biol. 5:469-478(2009).
     PubMed=19465933; DOI=10.1038/nchembio.178
[E1] https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=C80

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