Turner, G. C., Du, F., Varshavsky, A. (2000) Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway. Nature, 405 (6786). pp. 579-583. ISSN 00280836 (ISSN)
Abstract
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 (refs 1-3). 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 (ref. 5). 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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | ubiquitin allosterism amino terminal sequence article enzyme activation nonhuman positive feedback priority journal protein binding protein degradation protein expression protein targeting protein transport regulatory mechanism signal transduction Allosteric Regulation Amino Acid Substitution Binding Sites Biological Transport Carrier Proteins Dipeptides Feedback Fungal Proteins Gene Expression Regulation, Fungal Homeodomain Proteins Ligases Membrane Proteins Membrane Transport Proteins Peptides Saccharomyces cerevisiae Saccharomyces cerevisiae Proteins Transcription Factors Transcription, Genetic Ubiquitin-Protein Ligases Ubiquitins |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein receptor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > ubiquitin ligase |
| CSHL Authors: | |
| Communities: | CSHL labs > Turner lab |
| Depositing User: | CSHL Librarian |
| Date: | 2000 |
| Date Deposited: | 11 Apr 2012 14:54 |
| Last Modified: | 14 Mar 2013 16:19 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/26144 |
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