Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

Loss of ATE1-mediated arginylation leads to impaired platelet myosin phosphorylation, clot retraction, and in vivo thrombosis formation.
L. Lian, A. Suzuki, V. Hayes, S. Saha, X. Han, T. Xu, J. R. Yates III, M. Poncz, A. Kashina, and C. S. Abrams (2014)
Haematologica 99, 554-560
   Abstract »    Full Text »    PDF »
Post-translational arginylation as a novel regulator of platelet function.
M. Bender and H. Falet (2014)
Haematologica 99, 402-404
   Full Text »    PDF »
UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy.
T. Tasaki, S. T. Kim, A. Zakrzewska, B. E. Lee, M. J. Kang, Y. D. Yoo, H. J. Cha-Molstad, J. Hwang, N. K. Soung, K. S. Sung, et al. (2013)
PNAS 110, 3800-3805
   Abstract »    Full Text »    PDF »
Characterization of Arginylation Branch of N-end Rule Pathway in G-protein-mediated Proliferation and Signaling of Cardiomyocytes.
M. J. Lee, D. E. Kim, A. Zakrzewska, Y. D. Yoo, S.-H. Kim, S. T. Kim, J. W. Seo, Y. S. Lee, G. W. Dorn II, U. Oh, et al. (2012)
J. Biol. Chem. 287, 24043-24052
   Abstract »    Full Text »    PDF »
The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments.
K. I. Piatkov, C. S. Brower, and A. Varshavsky (2012)
PNAS 109, E1839-E1847
   Abstract »    Full Text »    PDF »
Talin is cut out for intercellular adhesion.
B. Short (2012)
J. Cell Biol. 197, 693
   Full Text »    PDF »
Arginylation-dependent regulation of a proteolytic product of talin is essential for cell-cell adhesion.
F. Zhang, S. Saha, and A. Kashina (2012)
J. Cell Biol. 197, 819-836
   Abstract »    Full Text »    PDF »
The C-terminal Proteolytic Fragment of the Breast Cancer Susceptibility Type 1 Protein (BRCA1) Is Degraded by the N-end Rule Pathway.
Z. Xu, R. Payoe, and R. P. Fahlman (2012)
J. Biol. Chem. 287, 7495-7502
   Abstract »    Full Text »    PDF »
Thinking Outside of the "RGS Box": New Approaches to Therapeutic Targeting of Regulators of G Protein Signaling.
B. Sjogren and R. R. Neubig (2010)
Mol. Pharmacol. 78, 550-557
   Abstract »    Full Text »    PDF »
Mouse Dfa Is a Repressor of TATA-box Promoters and Interacts with the Abt1 Activator of Basal Transcription.
C. S. Brower, L. Veiga, R. H. Jones, and A. Varshavsky (2010)
J. Biol. Chem. 285, 17218-17234
   Abstract »    Full Text »    PDF »
Arginylation Regulates Intracellular Actin Polymer Level by Modulating Actin Properties and Binding of Capping and Severing Proteins.
S. Saha, M. M. Mundia, F. Zhang, R. W. Demers, F. Korobova, T. Svitkina, A. A. Perieteanu, J. F. Dawson, and A. Kashina (2010)
Mol. Biol. Cell 21, 1350-1361
   Abstract »    Full Text »    PDF »
UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination.
J. Y. An, E.-A. Kim, Y. Jiang, A. Zakrzewska, D. E. Kim, M. J. Lee, I. Mook-Jung, Y. Zhang, and Y. T. Kwon (2010)
PNAS 107, 1912-1917
   Abstract »    Full Text »    PDF »
The N-end rule pathway controls multiple functions during Arabidopsis shoot and leaf development.
E. Graciet, F. Walter, D. O Maoileidigh, S. Pollmann, E. M. Meyerowitz, A. Varshavsky, and F. Wellmer (2009)
PNAS 106, 13618-13623
   Abstract »    Full Text »    PDF »
The Substrate Recognition Domains of the N-end Rule Pathway.
T. Tasaki, A. Zakrzewska, D. D. Dudgeon, Y. Jiang, J. S. Lazo, and Y. T. Kwon (2009)
J. Biol. Chem. 284, 1884-1895
   Abstract »    Full Text »    PDF »
Discovery of Cellular Regulation by Protein Degradation.
A. Varshavsky (2008)
J. Biol. Chem. 283, 34469-34489
   Full Text »    PDF »
Regulation of peptide import through phosphorylation of Ubr1, the ubiquitin ligase of the N-end rule pathway.
C.-S. Hwang and A. Varshavsky (2008)
PNAS 105, 19188-19193
   Abstract »    Full Text »    PDF »
Arginyltransferase regulates alpha cardiac actin function, myofibril formation and contractility during heart development.
R. Rai, C. C. L. Wong, T. Xu, N. A. Leu, D. W. Dong, C. Guo, K. J. McLaughlin, J. R. Yates III, and A. Kashina (2008)
Development 135, 3881-3889
   Abstract »    Full Text »    PDF »
Amino Acids Induce Peptide Uptake via Accelerated Degradation of CUP9, the Transcriptional Repressor of the PTR2 Peptide Transporter.
Z. Xia, G. C. Turner, C.-S. Hwang, C. Byrd, and A. Varshavsky (2008)
J. Biol. Chem. 283, 28958-28968
   Abstract »    Full Text »    PDF »
Substrate-binding Sites of UBR1, the Ubiquitin Ligase of the N-end Rule Pathway.
Z. Xia, A. Webster, F. Du, K. Piatkov, M. Ghislain, and A. Varshavsky (2008)
J. Biol. Chem. 283, 24011-24028
   Abstract »    Full Text »    PDF »
The N-end rule pathway is a sensor of heme.
R.-G. Hu, H. Wang, Z. Xia, and A. Varshavsky (2008)
PNAS 105, 76-81
   Abstract »    Full Text »    PDF »
Synthetic heterovalent inhibitors targeting recognition E3 components of the N-end rule pathway.
M. J. Lee, K. Pal, T. Tasaki, S. Roy, Y. Jiang, J. Y. An, R. Banerjee, and Y. T. Kwon (2008)
PNAS 105, 100-105
   Abstract »    Full Text »    PDF »
Listeriolysin O Secreted by Listeria monocytogenes into the Host Cell Cytosol Is Degraded by the N-End Rule Pathway.
P. Schnupf, J. Zhou, A. Varshavsky, and D. A. Portnoy (2007)
Infect. Immun. 75, 5135-5147
   Abstract »    Full Text »    PDF »
Biochemical and Genetic Studies of UBR3, a Ubiquitin Ligase with a Function in Olfactory and Other Sensory Systems.
T. Tasaki, R. Sohr, Z. Xia, R. Hellweg, H. Hortnagl, A. Varshavsky, and Y. T. Kwon (2007)
J. Biol. Chem. 282, 18510-18520
   Abstract »    Full Text »    PDF »
Cardiopoietic programming of embryonic stem cells for tumor-free heart repair.
A. Behfar, C. Perez-Terzic, R. S. Faustino, D. K. Arrell, D. M. Hodgson, S. Yamada, M. Puceat, N. Niederlander, A. E Alekseev, L. V. Zingman, et al. (2007)
J. Exp. Med. 204, 405-420
   Abstract »    Full Text »    PDF »
Crystal structures of leucyl/phenylalanyl-tRNA-protein transferase and its complex with an aminoacyl-tRNA analog.
K. Suto, Y. Shimizu, K. Watanabe, T. Ueda, S. Fukai, O. Nureki, and K. Tomita (2006)
EMBO J. 25, 5942-5950
   Abstract »    Full Text »    PDF »
Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination: Insights From Model Organisms.
Y. Wang and H. G. Dohlman (2006)
Circ. Res. 99, 1305-1314
   Abstract »    Full Text »    PDF »
Arginyltransferase, Its Specificity, Putative Substrates, Bidirectional Promoter, and Splicing-derived Isoforms.
R.-G. Hu, C. S. Brower, H. Wang, I. V. Davydov, J. Sheng, J. Zhou, Y. T. Kwon, and A. Varshavsky (2006)
J. Biol. Chem. 281, 32559-32573
   Abstract »    Full Text »    PDF »
Molecular dissection of arginyltransferases guided by similarity to bacterial peptidoglycan synthases.
R. Rai, A. Mushegian, K. Makarova, and A. Kashina (2006)
EMBO Rep. 7, 800-805
   Abstract »    Full Text »    PDF »
Cell biology. Actin discrimination..
J. C. Bulinski (2006)
Science 313, 180-181
   Abstract »    Full Text »    PDF »
Arginylation of {beta}-Actin Regulates Actin Cytoskeleton and Cell Motility.
M. Karakozova, M. Kozak, C. C. L. Wong, A. O. Bailey, J. R. Yates III, A. Mogilner, H. Zebroski, and A. Kashina (2006)
Science 313, 192-196
   Abstract »    Full Text »    PDF »
Impaired neurogenesis and cardiovascular development in mice lacking the E3 ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway.
J. Y. An, J. W. Seo, T. Tasaki, M. J. Lee, A. Varshavsky, and Y. T. Kwon (2006)
PNAS 103, 6212-6217
   Abstract »    Full Text »    PDF »
Aminoacyl-transferases and the N-end rule pathway of prokaryotic/eukaryotic specificity in a human pathogen.
E. Graciet, R.-G. Hu, K. Piatkov, J. H. Rhee, E. M. Schwarz, and A. Varshavsky (2006)
PNAS 103, 3078-3083
   Abstract »    Full Text »    PDF »
A Novel Form of Neurotensin Post-translationally Modified by Arginylation.
E. Eriste, A. Norberg, D. Nepomuceno, C. Kuei, F. Kamme, D.-T. Tran, K. Strupat, H. Jornvall, C. Liu, T. W. Lovenberg, et al. (2005)
J. Biol. Chem. 280, 35089-35097
   Abstract »    Full Text »    PDF »
RGS4 and RGS5 are in vivo substrates of the N-end rule pathway.
M. J. Lee, T. Tasaki, K. Moroi, J. Y. An, S. Kimura, I. V. Davydov, and Y. T. Kwon (2005)
PNAS 102, 15030-15035
   Abstract »    Full Text »    PDF »
A Family of Mammalian E3 Ubiquitin Ligases That Contain the UBR Box Motif and Recognize N-Degrons.
T. Tasaki, L. C. F. Mulder, A. Iwamatsu, M. J. Lee, I. V. Davydov, A. Varshavsky, M. Muesing, and Y. T. Kwon (2005)
Mol. Cell. Biol. 25, 7120-7136
   Abstract »    Full Text »    PDF »
Identification of mammalian arginyltransferases that modify a specific subset of protein substrates.
R. Rai and A. Kashina (2005)
PNAS 102, 10123-10128
   Abstract »    Full Text »    PDF »
RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway.
J. Yin, Y. T. Kwon, A. Varshavsky, and W. Wang (2004)
Hum. Mol. Genet. 13, 2421-2430
   Abstract »    Full Text »    PDF »
The ubiquitin-proteasome system in cardiovascular diseases--a hypothesis extended.
J. Herrmann, A. Ciechanover, L. O Lerman, and A. Lerman (2004)
Cardiovasc Res 61, 11-21
   Abstract »    Full Text »    PDF »
Female Lethality and Apoptosis of Spermatocytes in Mice Lacking the UBR2 Ubiquitin Ligase of the N-End Rule Pathway.
Y. T. Kwon, Z. Xia, J. Y. An, T. Tasaki, I. V. Davydov, J. W. Seo, J. Sheng, Y. Xie, and A. Varshavsky (2003)
Mol. Cell. Biol. 23, 8255-8271
   Abstract »    Full Text »    PDF »
Tumor Suppression by a Rationally Designed Reversible Inhibitor of Methionine Aminopeptidase-2.
J. Wang, G. S. Sheppard, P. Lou, M. Kawai, N. BaMaung, S. A. Erickson, L. Tucker-Garcia, C. Park, J. Bouska, Y.-C. Wang, et al. (2003)
Cancer Res. 63, 7861-7869
   Abstract »    Full Text »    PDF »
PRT1 of Arabidopsis Is a Ubiquitin Protein Ligase of the Plant N-End Rule Pathway with Specificity for Aromatic Amino-Terminal Residues.
S. Stary, X.-j. Yin, T. Potuschak, P. Schlogelhofer, V. Nizhynska, and A. Bachmair (2003)
Plant Physiology 133, 1360-1366
   Abstract »    Full Text »    PDF »
Plasma Protein Synthesis Measurements Using a Proteomics Strategy.
H. M. H. van Eijk and N. E. P. Deutz (2003)
J. Nutr. 133, 2084S-2089
   Abstract »    Full Text »    PDF »
{gamma}2 subunit of G protein heterotrimer is an N-end rule ubiquitylation substrate.
M. H. Hamilton, L. A. Cook, T. R. McRackan, K. L. Schey, and J. D. Hildebrandt (2003)
PNAS 100, 5081-5086
   Abstract »    Full Text »    PDF »
Control of protein life-span by N-terminal methionine excision.
C. Giglione, O. Vallon, and T. Meinnel (2003)
EMBO J. 22, 13-23
   Abstract »    Full Text »    PDF »
Dissection of c-MOS degron.
J. Sheng, A. Kumagai, W. G. Dunphy, and A. Varshavsky (2002)
EMBO J. 21, 6061-6071
   Abstract »    Full Text »    PDF »
Pairs of dipeptides synergistically activate the binding of substrate by ubiquitin ligase through dissociation of its autoinhibitory domain.
F. Du, F. Navarro-Garcia, Z. Xia, T. Tasaki, and A. Varshavsky (2002)
PNAS 99, 14110-14115
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882