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PROSITE documentation PDOC51771

CGT/MARTX cysteine protease (CPD) domain profile





Description

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 β-sheet that is surrounded by α-helices. Additional β-strands at the C-terminus form a subdomain known as the β-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 α-toxin (Tcnα).
  • 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.

Last update:

August 2015 / First entry.

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Technical section

PROSITE method (with tools and information) covered by this documentation:

CGT_MARTX_CPD, PS51771; CGT/MARTX cysteine protease (CPD) domain profile  (MATRIX)


References

1AuthorsEgerer M. Satchell K.J.F.
TitleInositol hexakisphosphate-induced autoprocessing of large bacterial protein toxins.
SourcePLoS Pathog. 6:E1000942-E1000942(2010).
PubMed ID20628577
DOI10.1371/journal.ppat.1000942

2AuthorsSheahan K.-L. Cordero C.L. Satchell K.J.F.
TitleAutoprocessing of the Vibrio cholerae RTX toxin by the cysteine protease domain.
SourceEMBO J. 26:2552-2561(2007).
PubMed ID17464284
DOI10.1038/sj.emboj.7601700

3AuthorsLupardus P.J. Shen A. Bogyo M. Garcia K.C.
TitleSmall molecule-induced allosteric activation of the Vibrio cholerae RTX cysteine protease domain.
SourceScience 322:265-268(2008).
PubMed ID18845756
DOI10.1126/science.1162403

4AuthorsShen A. Lupardus P.J. Albrow V.E. Guzzetta A. Powers J.C. Garcia K.C. Bogyo M.
TitleMechanistic and structural insights into the proteolytic activation of Vibrio cholerae MARTX toxin.
SourceNat. Chem. Biol. 5:469-478(2009).
PubMed ID19465933
DOI10.1038/nchembio.178

E1Titlehttps://www.ebi.ac.uk/merops/cgi-bin/famsum?family=C80



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