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Biochemical and Genetic Studies of UBR3, a Ubiquitin Ligase with a Function in Olfactory and Other Sensory Systems

Tasaki, Takafumi and Sohr, Reinhard and Xia, Zanxian and Hellweg, Rainer and Hörtnagl, Heidi and Varshavsky, Alexander and Kwon, Yong Tae (2007) Biochemical and Genetic Studies of UBR3, a Ubiquitin Ligase with a Function in Olfactory and Other Sensory Systems. Journal of Biological Chemistry, 282 (25). pp. 18510-18520. ISSN 0021-9258. doi:10.1074/jbc.M701894200.

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Our previous work identified E3 ubiquitin ligases, termed UBR1-UBR7, that contain the ~70-residue UBR box, a motif important for the targeting of N-end rule substrates. In this pathway, specific N-terminal residues of substrates are recognized as degradation signals by UBR box-containing E3s that include UBR1, UBR2, UBR4, and UBR5. The other E3s of this set, UBR3, UBR6, and UBR7, remained uncharacterized. Here we describe the cloning and analyses of mouse UBR3. The similarities of UBR3 to the UBR1 and UBR2 E3s of the N-end rule pathway include the RING and UBR domains. We show that HR6A and HR6B, the E2 enzymes that bind to UBR1 and UBR2, also interact with UBR3. However, in contrast to UBR1 and UBR2, UBR3 does not recognize N-end rule substrates. We also constructed UBR3-lacking mouse strains. In the 129SvImJ background, UBR3-/- mice died during embryogenesis, whereas the C57BL/6 background UBR3-/- mice exhibited neonatal lethality and suckling impairment that could be partially rescued by litter size reduction. The adult UBR3-/- mice had female-specific behavioral anosmia. Cells of the olfactory pathway were found to express beta-galactosidase (LacZ) that marked the deletion/disruption UBR3- allele. The UBR3-specific LacZ expression was also prominent in cells of the touch, vision, hearing, and taste systems, suggesting a regulatory role of UBR3 in sensory pathways, including olfaction. By analogy with functions of the UBR domain in the N-end rule pathway, we propose that the UBR box of UBR3 may recognize small compounds that modulate the targeting, by this E3, of its currently unknown substrates.

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Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2007 the American Society for Biochemistry and Molecular Biology. Received for publication, March 5, 2007, and in revised form, April 24, 2007. Originally published In Press as doi:10.1074/jbc.M701894200 on April 26, 2007. We are grateful to Jai Wha Seo for genotyping and maintaining mouse strains, to S. Pease (Caltech) for assistance with ES cell work, to B. Kennedy (Caltech) and the staff of the animal facility at the University of Pittsburgh for the care and maintenance of mice, and to A. Arnswald and A. Bunge for excellent technical assistance. The nucleotide sequence(s) reported in this paper has been submitted to the Gen-BankTM/EBI Data Bank with accession number(s) DQ924536. This work was supported by National Institutes of Health Grants GM69482, GM074000, and HL083365 (to Y.T.K.) and GM31530 and DK39520 (to A.V.) and also by the grants from the American Heart Association (to Y.T.K.), the Ellison Medical Foundation (to A. V.), and the Charité-Universitätsmedizin Berlin (to R.S., R.H., and H.H.). 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.
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Ellison Medical FoundationUNSPECIFIED
Charité-Universitätsmedizin BerlinUNSPECIFIED
Issue or Number:25
Record Number:CaltechAUTHORS:TASjbc07
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ID Code:8513
Deposited By: Archive Administrator
Deposited On:17 Aug 2007
Last Modified:08 Nov 2021 20:50

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