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An Essential Role of N-Terminal Arginylation in Cardiovascular Development

Science  05 Jul 2002:
Vol. 297, Issue 5578, pp. 96-99
DOI: 10.1126/science.1069531

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Abstract

The enzymatic conjugation of arginine to the N-termini of proteins is a part of the ubiquitin-dependent N-end rule pathway of protein degradation. In mammals, three N-terminal residues—aspartate, glutamate, and cysteine—are substrates for arginylation. The mouseATE1 gene encodes a family of Arg-tRNA-protein transferases (R-transferases) that mediate N-terminal arginylation. We constructed ATE1-lacking mouse strains and found thatATE1 −/− embryos die with defects in heart development and in angiogenic remodeling of the early vascular plexus. Through biochemical analyses, we show that N-terminal cysteine, in contrast to N-terminal aspartate and glutamate, is oxidized before its arginylation by R-transferase, suggesting that the arginylation branch of the N-end rule pathway functions as an oxygen sensor.

  • * These authors contributed equally to this work.

  • Present address: IGEN International Inc., 16020 Industrial Drive, Gaithersburg, MD 20877, USA.

  • To whom correspondence should be addressed. E-mail: avarsh{at}caltech.edu

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