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Molecular and Cellular Biology, July 2002, p. 4902-4913, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4902-4913.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Rad23 Promotes the Targeting of Proteolytic Substrates to the Proteasome

Li Chen and Kiran Madura*

Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Received 27 November 2001/ Returned for modification 23 January 2002/ Accepted 6 March 2002

Rad23 contains a ubiquitin-like domain (UbLR23) that interacts with catalytically active proteasomes and two ubiquitin (Ub)-associated (UBA) sequences that bind Ub. The UBA domains can bind Ub in vitro, although the significance of this interaction in vivo is poorly understood. Rad23 can interfere with the assembly of multi-Ub chains in vitro, and high-level expression caused stabilization of proteolytic substrates in vivo. We report here that Rad23 interacts with ubiquitinated cellular proteins through the synergistic action of its UBA domains. Rad23 plays an overlapping role with Rpn10, a proteasome-associated multi-Ub chain binding protein. Mutations in the UBA domains prevent efficient interaction with ubiquitinated proteins and result in poor suppression of the growth and proteolytic defects of a rad23{Delta} rpn10{Delta} mutant. High-level expression of Rad23 revealed, for the first time, an interaction between ubiquitinated proteins and the proteasome. This increase was not observed in rpn10{Delta} mutants, suggesting that Rpn10 participates in the recognition of proteolytic substrates that are delivered by Rad23. Overexpression of UbLR23 caused stabilization of a model substrate, indicating that an unregulated UbLR23-proteasome interaction can interfere with the efficient delivery of proteolytic substrates by Rad23. Because the suppression of a rad23{Delta} rpn10{Delta} mutant phenotype required both UbLR23 and UBA domains, our findings support the hypothesis that Rad23 encodes a novel regulatory factor that translocates ubiquitinated substrates to the proteasome.

* Corresponding author. Mailing address: Department of Biochemistry, Room 628, Robert Wood Johnson Medical School, 675 Hoes La., Piscataway, NJ 08854. Phone: (732) 235-5602. Fax: (732) 235-4783. E-mail: maduraki{at}umdnj.edu.

Molecular and Cellular Biology, July 2002, p. 4902-4913, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4902-4913.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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