|PROSITE documentation PDOC51074|
Diphthamide is a unique post-translationally modified histidine residue found only in translation elongation factor 2 (eEF-2). It is conserved from archaebacteria to humans and serves as the target for diphteria toxin and Pseudomonas exotoxin A. These two toxins catalyze the transfer of ADP-ribose to diphtamide on eEF-2, thus inactivating eEF-2, halting cellular protein synthesis, and causing cell death .
The biosynthesis of diphtamide is dependent on at least five proteins, DPH1 to -5, and a still unidentified amidating enzyme. DPH3 and DPH4 share a conserved region which encodes a metal-binding (MB) domain. The DHP-type or CSL-type (named after the final conserved cysteine of the zinc finger and the next two residues) MB domain contains a Cys-X-Cys...Cys-X2-Cys motif which tetrahedrically coordinates both Fe and Zn. The Fe containing DPH-type MBD has an electron transfer activity [2,3,4,5,6,7].
The DPH-type MB domain consists of a three-stranded β-sandwich with one sheet comprising two parallel strands: (i) β1 and (ii) β6 and one anti-parallel strand: β5. The second sheet in the β-sandwich is comprised of strands β2, β3, and β4 running anti-parallel to each other. The two β-sheets are separated by a short stretch α-helix (see <PDB:2L6L>) [4,6,7].
The profile we developed covers the whole DPH-type MB domain.Last update:
July 2019 / Text revised.
PROSITE method (with tools and information) covered by this documentation:
|Title||Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century.|
|2||Authors||Liu S. Leppla S.H.|
|Title||Retroviral insertional mutagenesis identifies a small protein required for synthesis of diphthamide, the target of bacterial ADP-ribosylating toxins.|
|Source||Mol. Cell 12:603-613(2003).|
|3||Authors||Liu S. Milne G.T. Kuremsky J.G. Fink G.R. Leppla S.H.|
|Title||Identification of the proteins required for biosynthesis of diphthamide, the target of bacterial ADP-ribosylating toxins on translation elongation factor 2.|
|Source||Mol. Cell. Biol. 24:9487-9497(2004).|
|4||Authors||Sun J. Zhang J. Wu F. Xu C. Li S. Zhao W. Wu Z. Wu J. Zhou C.-Z. Shi Y.|
|Title||Solution structure of Kti11p from Saccharomyces cerevisiae reveals a novel zinc-binding module.|
|5||Authors||Proudfoot M. Sanders S.A. Singer A. Zhang R. Brown G. Binkowski A. Xu L. Lukin J.A. Murzin A.G. Joachimiak A. Arrowsmith C.H. Edwards A.M. Savchenko A.V. Yakunin A.F.|
|Title||Biochemical and structural characterization of a novel family of cystathionine beta-synthase domain proteins fused to a Zn ribbon-like domain.|
|Source||J. Mol. Biol. 375:301-315(2008).|
|6||Authors||Thakur A. Chitoor B. Goswami A.V. Pareek G. Atreya H.S. D'Silva P.|
|Title||Structure and mechanistic insights into novel iron-mediated moonlighting functions of human J-protein cochaperone, Dph4.|
|Source||J. Biol. Chem. 287:13194-13205(2012).|
|7||Authors||Glatt S. Zabel R. Vonkova I. Kumar A. Netz D.J. Pierik A.J. Rybin V. Lill R. Gavin A.-C. Balbach J. Breunig K.D. Mueller C.W.|
|Title||Structure of the Kti11/Kti13 heterodimer and its double role in modifications of tRNA and eukaryotic elongation factor 2.|