Special Issue "Diphtheria Toxin"

Guest Editor
Dr. Daniel Gillet
IBiTec-S, SIMOPRO, CEA-Saclay / Bât. 152, 91191 Gif sur Yvette Cedex, France
Website: http://www-dsv.cea.fr/en/institutes/institute-of-biology-and-technology-saclay-ibitec-s/units/molecular-engineering-of-proteins-simopro/molecular-toxinology-and-biotechnology-laboratory-ltmb/toxin-membrane-interactions-d.-gillet
E-Mail: daniel.gillet@cea.fr
Phone: +33 1 69 08 76 46
Fax: +33 6 88 21 08 73

Dear Colleagues,

Diphtheria toxin was the first bacterial toxin to be discovered. It is among the best-known bacterial toxins acting inside cells. This exquisitely sophisticated piece of molecular machinery regroups three main distinct activities, each relying on very different biological properties: the recognition of a ubiquitous cell-surface protein in order to get internalized by cells, the capacity to cross the membrane barrier of intracellular trafficking compartments and a highly specific catalytic activity capable of neutralizing protein synthesis. Anti-diphtheria toxin vaccination with toxoid started almost a century ago and still has a tremendous impact on public health, preventing each year the deaths of tens of thousands of children. More recently, sophisticated protein engineering of diphtheria toxin led to many biotechnological applications for research, and to the first approved anti-tumor targeted toxin for the treatment of lymphomas. However, there is still a lot to discover about the molecular details of the various steps of the mechanism of action of the toxin, as modern biology enables to understand molecular events at atomic resolution and in living cells. There is little doubt that in the future, several new biological drugs will be based on modified fragments of this fascinating protein.

Dr. Daniel Gillet
Guest Editor

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• diphtheria toxin
• toxoid
• targeted toxin
• membrane translocation
• HB-EGF
• ADP-ribosylation

Type of Paper: Review
Title: PH-Triggered Conformational Switching along Membrane Insertion Pathway of the Diphtheria Toxin T-Domain
Author: Alexey S. Ladokhin
Affiliation: Department of Biochemistry and Molecular Biology, Kansas City, KS 66160-7421, USA; E-Mail: aladokhin@kumc.edu (A.S.L.)
Abstract: The translocation (T) domain plays a key role in the action of diphtheria toxin and is responsible for transferring the catalytic domain across the endosomal membrane into the cytosol in response to acidification. Deciphering molecular mechanism of pH-dependent refolding and membrane insertion of the T-domain, which is considered to be a paradigm for cell entry of other bacterial toxins, reveals general physicochemical principles underlying membrane protein assembly and signaling on membrane interfaces. Structure-function studies along the T-domain insertion pathway have been affected by the presence of multiple conformations at the same time, which hinders application of high-resolution structural techniques. Here we review recent progress in structural, functional and thermodynamic studies of the T-domain archived using a combination of site-selective fluorescence labeling with an array of spectroscopic techniques, such as FCS, FRET and fluorescence lifetime quenching. We also discuss the principles of conformational switching along the insertion pathway revealed by studies of a series of T-domain mutants with substitutions of histidine residues.