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An Essential Role of N-Terminal Arginylation in Cardiovascular Development
Yong Tae Kwon,*Anna S. Kashina,*Ilia V. Davydov,Rong-Gui Hu,Jee Young An,Jai Wha Seo,Fangyong Du,Alexander Varshavsky
The enzymatic conjugation of arginine to the N-termini of proteins
is a part of the ubiquitin-dependent N-end rule pathwayof 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-lackingmouse strains and found that
ATE1/ embryos die with defects in heart
development and in angiogenicremodeling of the early vascular plexus.
Through biochemical analyses,we show that N-terminal cysteine, in
contrast to N-terminal aspartateand glutamate, is oxidized before its
arginylation by R-transferase,suggesting that the arginylation branch
of the N-end rule pathwayfunctions 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.
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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