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

Hu, Rong-Gui and Brower, Christopher S. and Wang, Haiqing and Davydov, Ilia V. and Sheng, Jun and Zhou, Jianmin and Kwon, Yong Tae and Varshavsky, Alexander (2006) Arginyltransferase, Its Specificity, Putative Substrates, Bidirectional Promoter, and Splicing-derived Isoforms. Journal of Biological Chemistry, 281 (43). pp. 32559-32573. ISSN 0021-9258. https://resolver.caltech.edu/CaltechAUTHORS:HURjbc06

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Abstract

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.


Item Type:Article
ORCID:
AuthorORCID
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2006 the American Society for Biochemistry and Molecular Biology. Received for publication, May 8, 2006 , and in revised form, August 15, 2006. Originally published In Press as doi:10.1074/jbc.M604355200 on August 30, 2006 We thank N. Kendrick and J. Johansen (Kendrick Laboratories, Inc.) for two-dimensional electrophoresis; M. A. Gawinowicz (Columbia University) for mass spectrometric analyses; F. Rusnak, G. Hathaway, and J. Zhou (Caltech) for protein sequencing by Edman degradation; J. Arvizu, L. del Carmen Sandoval, B. W. Kennedy, and S. Pease (Caltech) for advice and assistance with mouse mutants; and E. Schwarz (Caltech) for advice on bioinformatic searches. We also thank E. Graciet for comments on the manuscript and acknowledge purification of the isoforms of mouse R-transferase by I. K. Nangiana and the late P. Snow (Protein Expression Center, Caltech). 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.
Funders:
Funding AgencyGrant Number
NIHGM31530
NIHDK39520
NIHGM069482
NIHGM074000
Ellison Medical FoundationUNSPECIFIED
American Heart AssociationUNSPECIFIED
Issue or Number:43
Record Number:CaltechAUTHORS:HURjbc06
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:HURjbc06
Alternative URL:http://dx.doi.org/10.1074/jbc.M604355200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5992
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:10 Nov 2006
Last Modified:02 Oct 2019 23:28

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