title: Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway.
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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena 91125, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Turner
authors.forename: F
authors.initials: F
authors.lastname: Du
authors.forename: A
authors.initials: A
authors.lastname: Varshavsky
mesh_terms: D000494:Allosteric Regulation; D019943:Amino Acid Substitution; D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism; D005246:Feedback; D005656:Fungal Proteins / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D018398:Homeodomain Proteins / Q000378:metabolism; D008025:Ligases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D010455:Peptides / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C090457:CUP9 protein, S cerevisiae; D002352:Carrier Proteins; D004151:Dipeptides; D005656:Fungal Proteins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C093495:PTR2 protein, S cerevisiae; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D014452:Ubiquitins; C066066:UBR1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D008025:Ligases