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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 [1].
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.
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.
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.
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