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

Graciet, Emmanuelle and Hu, Rong-Gui and Piatkov, Konstantin and Rhee, Joon Haeng and Schwartz, Erich M. and Varshavsky, Alexander (2006) Aminoacyl-transferases and the N-end rule pathway of prokaryotic/eukaryotic specificity in a human pathogen. Proceedings of the National Academy of Sciences of the United States of America, 103 (9). pp. 3078-3083. ISSN 0027-8424. PMCID PMC1413915. https://resolver.caltech.edu/CaltechAUTHORS:GRApnas06a

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413915/PubMed CentralArticle
https://doi.org/10.1073/pnas.0511224103DOIUNSPECIFIED
https://doi.org/10.1073/pnas.0511224103DOIUNSPECIFIED
ORCID:
AuthorORCID
Varshavsky, Alexander0000-0002-4011-258X
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.
Funders:
Funding AgencyGrant Number
NIHDK39520
NIHGM31530
Human Frontier Science ProgramUNSPECIFIED
Colvin FoundationUNSPECIFIED
Subject Keywords:proteolysis; ClpAP; ClpS; Aat; bacterial protein transferase
Issue or Number:9
PubMed Central ID:PMC1413915
Record Number:CaltechAUTHORS:GRApnas06a
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:GRApnas06a
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5443
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:17 Oct 2006
Last Modified:02 Oct 2019 23:22

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