An essential role of N-terminal arginylation in cardiovascular development.
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.
Kwon
Yong Tae
YT
Division of Biology, 147-75, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
Kashina
Anna S
AS
Davydov
Ilia V
IV
Hu
Rong-Gui
RG
An
Jee Young
JY
Seo
Jai Wha
JW
Du
Fangyong
F
Varshavsky
Alexander
A
D000478:Alkylation; D019881:Aminoacyltransferases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000196:embryology; D001120:Arginine / Q000378:metabolism*; D001224:Aspartic Acid / Q000378:metabolism; D001808:Blood Vessels / Q000196:embryology*; D002460:Cell Line; D003544:Cysteic Acid / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology; D006343:Heart Septal Defects / Q000196:embryology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism*; D011651:Pulmonary Artery / Q000196:embryology; D020710:RGS Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013441:Sulfinic Acids / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011506:Proteins; D020710:RGS Proteins; D011994:Recombinant Proteins; D013441:Sulfinic Acids; D014157:Transcription Factors; C098799:RGS4 protein; D001224:Aspartic Acid; D018698:Glutamic Acid; D001120:Arginine; D003544:Cysteic Acid; D019881:Aminoacyltransferases; C019727:arginyltransferase; D003545:Cysteine