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Published March 14, 2000 | Published
Journal Article Open

Physical association of ubiquitin ligases and the 26S proteasome


The ubiquitin (Ub) system recognizes degradation signals of the target proteins through the E3 components of E3-E2 Ub ligases. A targeted substrate bears a covalently linked multi-Ub chain and is degraded by the ATP-dependent 26S proteasome, which consists of the 20S core protease and two 19S particles. The latter mediate the binding and unfolding of a substrate protein before its transfer to the interior of the 20S core. It is unclear how a targeted substrate is delivered to the 26S proteasome, inasmuch as Rpn10p, the only known proteasomal subunit that binds multi-Ub chains, has been found to he not essential for degradation of many proteins in the yeast Saccharomyces cerevisiae. Here we show that Ubr1p and Ufd4p, the E3 components of two distinct Ub ligases, directly interact with the 26S proteasome. Specifically, Ubr1p is shown to bind to the Rpn2p, Rpt1p, and Rpt6p proteins of the 19S particle, and Ufd4p is shown to bind to Rpt6p. These and related results suggest that a substrate-bound Ub ligase participates in the delivery of substrates to the proteasome, because of affinity between the ligase's E3 component and specific proteins of the 19S particle.

Additional Information

© 2000 by the National Academy of Sciences. Contributed by Alexander Varshavsky, January 19, 2000. Published online before print February 25, 2000, 10.1073/pnas.060025497. We thank F. Du and A. Webster for the gifts of purified FLAG-Ubr1p and the UPR-based plasmids, C. Pickart for isolated multi-Ub chains, H. Rao for the strain AVY107, and E. Johnson for the pRS313UFD4 plasmid. This work was supported by grants to A.V. from the National Institutes of Health (GM31530 and DK39520). Y.X. was supported in part by a postdoctoral fellowship from the National Institutes of Health. 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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