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Published July 7, 1998 | Published
Journal Article Open

The mouse and human genes encoding the recognition component of the N-end rule pathway


The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. The N-end rule pathway is one proteolytic pathway of the ubiquitin system. The recognition component of this pathway, called N-recognin or E3, binds to a destabilizing N-terminal residue of a substrate protein and participates in the formation of a substrate-linked multiubiquitin chain. We report the cloning of the mouse and human Ubr1 cDNAs and genes that encode a mammalian N-recognin called E3 alpha. Mouse UBR1p (E3 alpha) is a 1,757-residue (200-kDa) protein that contains regions of sequence similarity to the 225-kDa Ubr1p of the yeast Saccharomyces cerevisiae. Mouse and human UBR1p have apparent homologs in other eukaryotes as well, thus defining a distinct family of proteins, the UBR family. The residues essential for substrate recognition by the yeast Ubr1p are conserved in the mouse UBR1p. The regions of similarity among the UBR family members include a putative zinc finger and RING-H2 finger, another zinc-binding domain. Ubr1 is located in the middle of mouse chromosome 2 and in the syntenic 15q15-q21.1 region of human chromosome 15. Mouse Ubr1 spans approximate to 120 kilobases of genomic DNA and contains approximate to 50 exons. Ubr1 is ubiquitously expressed in adults, with skeletal muscle and heart being the sites of highest expression. In mouse embryos, the Ubr1 expression is highest in the branchial arches and in the tail and limb buds. The cloning of Ubr1 makes possible the construction of Ubr1-lacking mouse strains, a prerequisite for the functional understanding of the mammalian N-end rule pathway.

Additional Information

© 1998 by the National Academy of Sciences. Contributed by Alexander Varshavsky, May 5, 1998. We are grateful to A. Webster and M. Ghislain for permission to cite their unpublished data. We thank members of the Varshavsky lab, especially I. V. Davydov, for helpful discussions, and L. Peck, G. Turner, H. Rao, A. Kashina, and F. Du for comments on the manuscript. Y.T.K. thanks B. Yu for sharing his Northern hybridization data on human b-actin mRNA. We gratefully acknowledge the sequencing of K. lactis UBR1 by P. Waller. N.G.C. and N.A.J. thank D. J. Gilbert and D. B. Householder for excellent technical assistance. D.K.G. was a Scholar of the Leukemia Society of America. This study was supported by National Institutes of Health grants to A.V. (DK39520 and GM31530), V.A.F. (NS29542), and D.K.G. (GM45314), and by a grant to N.G.C. from the National Cancer Institute. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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