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Published February 28, 2006 | Published
Journal Article Open

Aminoacyl-transferases and the N-end rule pathway of prokaryotic/eukaryotic specificity in a human pathogen


The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Primary destabilizing N-terminal residues (Ndp) are recognized directly by the targeting machinery. The recognition of secondary destabilizing N-terminal residues (Nds) is preceded by conjugation of an Ndp residue to Nds of a polypeptide substrate. In eukaryotes, ATE1-encoded arginyl-transferases (RD,E,C*-transferases) conjugate Arg (R), an Ndp residue, to Nds residues Asp (D), Glu (E), or oxidized Cys residue (C*). Ubiquitin ligases recognize the N-terminal Arg of a substrate and target the (ubiquitylated) substrate to the proteasome. In prokaryotes such as Escherichia coli, Ndp residues Leu (L) or Phe (F) are conjugated, by the aat-encoded Leu/Phe-transferase (L/FK,R-transferase), to N-terminal Arg or Lys, which are Nds in prokaryotes but Ndp in eukaryotes. In prokaryotes, substrates bearing the Ndp residues Leu, Phe, Trp, or Tyr are degraded by the proteasome-like ClpAP protease. Despite enzymological similarities between eukaryotic RD,E,C*-transferases and prokaryotic L/FK,R-transferases, there is no significant sequelogy (sequence similarity) between them. We identified an aminoacyl-transferase, termed Bpt, in the human pathogen Vibrio vulnificus. Although it is a sequelog of eukaryotic RD,E,C*-transferases, this prokaryotic transferase exhibits a "hybrid" specificity, conjugating Ndp Leu to Nds Asp or Glu. Another aminoacyl-transferase, termed ATEL1, of the eukaryotic pathogen Plasmodium falciparum, is a sequelog of prokaryotic L/FK,R-transferases (Aat), but has the specificity of eukaryotic RD,E,C*-transferases (ATE1). Phylogenetic analysis suggests that the substrate specificity of R-transferases arose by two distinct routes during the evolution of eukaryotes.

Additional Information

© 2006 by the National Academy of Sciences Contributed by Alexander Varshavsky, December 28, 2005. Published online before print February 21, 2006, 10.1073/pnas.0511224103 We thank J. D. Oliver (University of North Carolina, Charlotte) for the V. vulnificus C7184 translucent strain, F. Wellmer (California Institute of Technology) for the A. tumefaciens strain C58, T. Kaneko (Kazusa DNA Research Institute, Chiba, Japan) for genomic DNA of M. loti, L.-I. Hor (National Cheng-Kung University, Taiwan) for the plasmid pJRD215, the Malaria Research and Reference Reagent Resource Center (MR4; Manassas, VA) for P. falciparum 3D7 genomic DNA, which was contributed to MR4 by D. J. Carucci (National Institutes of Health, Bethesda), and D. Ladant (Institut Pasteur, Paris) for the E. coli-based two-hybrid system. This study was supported by National Institutes of Health Grants DK39520 and GM31530 (to A.V.). E.G. and K.P. were supported, respectively, by the International Human Frontier Science Program and Colvin postdoctoral fellowships. Author contributions: E.G., R.-G.H., and A.V. designed research; E.G., R.-G.H., and K.P. performed research; E.G., K.P., J.H.R., E.M.S., and A.V. contributed new reagents/analytic tools; E.G., R.-G.H., K.P., J.H.R., E.M.S., and A.V. analyzed data; and E.G. and A.V. wrote the paper. Conflict of interest statement: No conflicts declared.

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