The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators

被引:245
作者
Hu, RG
Sheng, J
Qi, X
Xu, ZM
Takahashi, TT
Varshavsky, A [1 ]
机构
[1] CALTECH, Div Biol, Pasadena, CA 91125 USA
[2] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nature04027
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The conjugation of arginine to proteins is a part of the N- end rule pathway of protein degradation. Three amino (N)-terminal residues - aspartate, glutamate and cysteine - are arginylated by ATE1-encoded arginyl-transferases. Here we report that oxidation of N- terminal cysteine is essential for its arginylation. The in vivo oxidation of N- terminal cysteine, before its arginylation, is shown to require nitric oxide. We reconstituted this process in vitro as well. The levels of regulatory proteins bearing N- terminal cysteine, such as RGS4, RGS5 and RGS16, are greatly increased in mouse ATE1(-/-) embryos, which lack arginylation. Stabilization of these proteins, the first physiological substrates of mammalian N- end rule pathway, may underlie cardiovascular defects in ATE1(-/-) embryos. Our findings identify the N- end rule pathway as a new nitric oxide sensor that functions through its ability to destroy specific regulatory proteins bearing N- terminal cysteine, at rates controlled by nitric oxide and apparently by oxygen as well.
引用
收藏
页码:981 / 986
页数:6
相关论文
共 43 条
[1]   Identification and characterization of regulator of G protein signaling 4 (RGS4) as a novel inhibitor of tubulogenesis: RGS4 inhibits mitogen-activated protein kinases and vascular endothelial growth factor signaling [J].
Albig, AR ;
Schiemann, WP .
MOLECULAR BIOLOGY OF THE CELL, 2005, 16 (02) :609-625
[2]   THE DEGRADATION SIGNAL IN A SHORT-LIVED PROTEIN [J].
BACHMAIR, A ;
VARSHAVSKY, A .
CELL, 1989, 56 (06) :1019-1032
[3]   INVIVO HALF-LIFE OF A PROTEIN IS A FUNCTION OF ITS AMINO-TERMINAL RESIDUE [J].
BACHMAIR, A ;
FINLEY, D ;
VARSHAVSKY, A .
SCIENCE, 1986, 234 (4773) :179-186
[4]   YEAST N-TERMINAL AMIDASE - A NEW ENZYME AND COMPONENT OF THE N-END RULE PATHWAY [J].
BAKER, RT ;
VARSHAVSKY, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (20) :12065-12074
[5]  
BALZI E, 1990, J BIOL CHEM, V265, P7464
[6]   Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms [J].
Barouch, LA ;
Harrison, RW ;
Skaf, MW ;
Rosas, GO ;
Cappola, TP ;
Kobeissi, ZA ;
Hobai, IA ;
Lemmon, CA ;
Burnett, AL ;
O'Rourke, B ;
Rodriguez, ER ;
Huang, PL ;
Lima, JAC ;
Berkowitz, DE ;
Hare, JM .
NATURE, 2002, 416 (6878) :337-340
[7]   Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers [J].
Becker, K ;
Savvides, SN ;
Keese, M ;
Schirmer, RH ;
Karplus, PA .
NATURE STRUCTURAL BIOLOGY, 1998, 5 (04) :267-271
[8]   Arginine methylation: An emerging regulator of protein function [J].
Bedford, MT ;
Richard, S .
MOLECULAR CELL, 2005, 18 (03) :263-272
[9]   Mammalian RGS proteins: Barbarians at the gate [J].
Berman, DM ;
Gilman, AG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (03) :1269-1272
[10]   Novel neural modulators [J].
Boehning, D ;
Snyder, SH .
ANNUAL REVIEW OF NEUROSCIENCE, 2003, 26 :105-131