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Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway

Turner, Glenn C. and Du, Fangyong and Varshavsky, Alexander (2000) Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway. Nature, 405 (6786). p. 579. ISSN 0028-0836. doi:10.1038/35014629.

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Protein degradation by the ubiquitin system controls the intracellular concentrations of many regulatory proteins. A protein substrate of the ubiquitin system is conjugated to ubiquitin through the action of three enzymes, E1, E2 and E3, with the degradation signal (degron) of the substrate recognized by E3. The resulting multi-ubiquitylated substrate is degraded by the 26S proteasome. Here we describe the physiological regulation of a ubiquitin-dependent pathway through allosteric modulation of its E3 activity by small compounds. Ubr1, the E3 enzyme of the N-end rule pathway (a ubiquitin-dependent proteolytic system) in Saccharomyces cerevisiae mediates the degradation of Cup9, a transcriptional repressor of the peptide transporter Ptr2. Ubr1 also targets proteins that have destabilizing amino-terminal residues. We show that the degradation of Cup9 is allosterically activated by dipeptides with destabilizing N-terminal residues. In the resulting positive feedback circuit, imported dipeptides bind to Ubr1 and accelerate the Ubr1-dependent degradation of Cup9, thereby de-repressing the expression of Ptr2 and increasing the cell's capacity to import peptides. These findings identify the physiological rationale for the targeting of Cup9 by Ubr1, and indicate that small compounds may regulate other ubiquitin-dependent pathways.

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Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2000 Macmillan Magazines Ltd. Received 5 January 2000; Accepted 5 April 2000. We thank A. Webster for her valuable contributions to establishing the in vitro system, and R. Deshaies, J. Dohmen, L. Prakash, H. Rao and J. Sheng for their gifts of plasmids and strains. We also thank C. Byrd, H. Rao, T. Iverson and especially R. Deshaies for helpful discussions and comments on the manuscript. This work was supported by grants to A.V. from the NIH.
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Issue or Number:6786
Record Number:CaltechAUTHORS:20150330-105345474
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Official Citation:Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway p579 Glenn C. Turner, Fangyong Du and Alexander Varshavsky doi:10.1038/35014629
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:56213
Deposited By: Ruth Sustaita
Deposited On:30 Mar 2015 19:47
Last Modified:10 Nov 2021 20:56

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