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J. Biol. Chem., Vol. 281, Issue 43, 32559-32573, October 27, 2006

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Arginyltransferase, Its Specificity, Putative Substrates, Bidirectional Promoter, and Splicing-derived Isoforms^*

Rong-Gui Hu, Christopher S. Brower, Haiqing Wang, Ilia V. Davydov, Jun Sheng, Jianmin Zhou, Yong Tae Kwon^¶, and Alexander Varshavsky¹

From the Division of Biology, California Institute of Technology, Pasadena, California 91125, Meso Scale Discovery, Gaithersburg, Maryland 20877, and ^¶Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Substrates of the N-end rule pathway include proteins with destabilizing N-terminal residues. Three of them, Asp, Glu, and (oxidized) Cys, function through their conjugation to Arg, one of destabilizing N-terminal residues that are recognized directly by the pathway's ubiquitin ligases. The conjugation of Arg is mediated by arginyltransferase, encoded by ATE1. Through its regulated degradation of specific proteins, the arginylation branch of the N-end rule pathway mediates, in particular, the cardiovascular development, the fidelity of chromosome segregation, and the control of signaling by nitric oxide. We show that mouse ATE1 specifies at least six mRNA isoforms, which are produced through alternative splicing, encode enzymatically active arginyltransferases, and are expressed at varying levels in mouse tissues. We also show that the ATE1 promoter is bidirectional, mediating the expression of both ATE1 and an oppositely oriented, previously uncharacterized gene. In addition, we identified GRP78 (glucose-regulated protein 78) and protein-disulfide isomerase as putative physiological substrates of arginyltransferase. Purified isoforms of arginyltransferase that contain the alternative first exons differentially arginylate these proteins in extract from ATE1^-/- embryos, suggesting that specific isoforms may have distinct functions. Although the N-end rule pathway is apparently confined to the cytosol and the nucleus, and although GRP78 and protein-disulfide isomerase are located largely in the endoplasmic reticulum, recent evidence suggests that these proteins are also present in the cytosol and other compartments in vivo, where they may become N-end rule substrates.

Received for publication, May 8, 2006 , and in revised form, August 15, 2006.

^* This work was supported by National Institutes of Health Grants GM31530, DK39520 (to A. V.), GM069482, and GM074000 (to Y. T. K.) and by grants from the Ellison Medical Foundation (to A. V.) and the American Heart Association (to Y. T. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 626-395-3785; Fax: 626-440-9821; E-mail: avarsh{at}caltech.edu.

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