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Science 297 (5578): 96-99

Copyright © 2002 by the American Association for the Advancement of Science

An Essential Role of N-Terminal Arginylation in Cardiovascular Development

Yong Tae Kwon,* Anna S. Kashina,* Ilia V. Davydov,dagger Rong-Gui Hu, Jee Young An, Jai Wha Seo, Fangyong Du, Alexander Varshavskyddagger

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 mouse ATE1 gene encodes a family of Arg-tRNA-protein transferases (R-transferases) that mediate N-terminal arginylation. We constructed ATE1-lacking mouse strains and found that ATE1-/- 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.

Division of Biology, 147-75, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
*   These authors contributed equally to this work.

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

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

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