Toxin Structure, Delivery and Action


Varol B., Özerman Edis B., Bektaş M.

in: Corynebacterium diphtheriae and Related Toxigenic Species: Genomics, Pathogenicity and Applications, Varol B.,Özerman Edis B.,Bektaş M., Editor, Springer Netherlands, İstanbul, pp.83-94, 2013

  • Publication Type: Book Chapter / Chapter Research Book
  • Publication Date: 2013
  • Publisher: Springer Netherlands
  • City: İstanbul
  • Page Numbers: pp.83-94
  • Editors: Varol B.,Özerman Edis B.,Bektaş M., Editor
  • Istanbul University Affiliated: Yes

Abstract

Diphtheria toxin (DTx) consists of a 535 amino acids polypeptide and contains the following three domains: the amino terminal fragment A (FA or catalytic C-domain) that catalyses the transfer of an ADP-ribosyl group of NAD+ to a post-translationally modified histidine (diphthamide) residue on eukaryotic elongation factor 2 (eEF2) and inhibits protein synthesis. Fragment B (FB) consist of the carboxy terminal receptor-binding R-domain, and the translocation (or transmembrane) T-domain. Following binding to its cell surface receptor via R-domain, DTx is internalized through the clathrin-dependent endocytosis. The acid pH created in the early endosomes triggers a conformational change in the toxin leading to the insertion of the T and C-domains in the membrane. The catalytic domain is then translocated into the cytosol across the early endosomal membrane and protein synthesis inhibition occurs. DTx-induced cytotoxicity is versatile, and it includes DNA cleavage and the depolymerisation of actin filaments. FA can interact with both G and F-actin. The binding to the latter appears to take place at the plus end of the filament blocking further polymerisation and it was concluded that G-actin has an inhibitory effect on DTx nuclease activity.