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Molecular and Cellular Biology, August 2005, p. 7120-7136, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7120-7136.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Family of Mammalian E3 Ubiquitin Ligases That Contain the UBR Box Motif and Recognize N-Degrons

Takafumi Tasaki,1 Lubbertus C. F. Mulder,2 Akihiro Iwamatsu,3 Min Jae Lee,1 Ilia V. Davydov,4,{dagger} Alexander Varshavsky,4 Mark Muesing,2 and Yong Tae Kwon1*

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,1 Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016,2 Protein Research Network, Inc., Yokohama, Kanagawa 236-0004, Japan,3 Division of Biology, California Institute of Technology, Pasadena, California 911254

Received 15 March 2005/ Returned for modification 27 April 2005/ Accepted 13 May 2005

A subset of proteins targeted by the N-end rule pathway bear degradation signals called N-degrons, whose determinants include destabilizing N-terminal residues. Our previous work identified mouse UBR1 and UBR2 as E3 ubiquitin ligases that recognize N-degrons. Such E3s are called N-recognins. We report here that while double-mutant UBR1–/– UBR2–/– mice die as early embryos, the rescued UBR1–/– UBR2–/– fibroblasts still retain the N-end rule pathway, albeit of lower activity than that of wild-type fibroblasts. An affinity assay for proteins that bind to destabilizing N-terminal residues has identified, in addition to UBR1 and UBR2, a huge (570 kDa) mouse protein, termed UBR4, and also the 300-kDa UBR5, a previously characterized mammalian E3 known as EDD/hHYD. UBR1, UBR2, UBR4, and UBR5 shared a ~70-amino-acid zinc finger-like domain termed the UBR box. The mammalian genome encodes at least seven UBR box-containing proteins, which we propose to call UBR1 to UBR7. UBR1–/– UBR2–/– fibroblasts that have been made deficient in UBR4 as well (through RNA interference) were significantly impaired in the degradation of N-end rule substrates such as the Sindbis virus RNA polymerase nsP4 (bearing N-terminal Tyr) and the human immunodeficiency virus type 1 integrase (bearing N-terminal Phe). Our results establish the UBR box family as a unique class of E3 proteins that recognize N-degrons or structurally related determinants for ubiquitin-dependent proteolysis and perhaps other processes as well.

* Corresponding author. Mailing address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15261. Phone: 412-383-7994. Fax: 412-648-1664. E-mail: yok5{at}pitt.edu.

{dagger} Present address: Meso-Scale Discovery, 16020 Industrial Drive, Gaithersburg, MD 20877.

Molecular and Cellular Biology, August 2005, p. 7120-7136, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.7120-7136.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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