Proceedings of the National Academy of Sciences - PNAS, 2008-04, Vol.105 (14), p.5632-5637
2008
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- Autor(en) / Beteiligte
- Titel
- Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2008-04, Vol.105 (14), p.5632-5637
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2008
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The regulation of gene expression by the hormone auxin is a crucial mechanism in plant development. We have shown that the Arabidopsis F-box protein TIR1 is a receptor for auxin, and our recent structural work has revealed the molecular mechanism of auxin perception. TIR1 is the substrate receptor of the ubiquitin-ligase complex SCFTIR¹. Auxin binding enhances the interaction between TIR1 and its substrates, the Aux/IAA repressors, thereby promoting the ubiquitination and degradation of Aux/IAAs, altering the expression of hundreds of genes. TIR1 is the prototype of a new class of hormone receptor and the first example of an SCF ubiquitin-ligase modulated by a small molecule. Here, we describe the design, synthesis, and characterization of a series of auxin agonists and antagonists. We show these molecules are specific to TIR1-mediated events in Arabidopsis, and their mode of action in binding to TIR1 is confirmed by x-ray crystallographic analysis. Further, we demonstrate the utility of these probes for the analysis of TIR1-mediated auxin signaling in the moss Physcomitrella patens. Our work not only provides a useful tool for plant chemical biology but also demonstrates an example of a specific small-molecule inhibitor of F-box protein-substrate recruitment. Substrate recognition and subsequent ubiquitination by SCF-type ubiquitin ligases are central to many cellular processes in eukaryotes, and ubiquitin-ligase function is affected in several human diseases. Our work supports the idea that it may be possible to design small-molecule agents to modulate ubiquitin-ligase function therapeutically.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.0711146105Titel-ID: cdi_proquest_journals_201291215
- Format
- –
- Schlagworte
- Antiauxins, Arabidopsis, Arabidopsis Proteins - agonists, Arabidopsis Proteins - antagonists & inhibitors, Arabidopsis Proteins - metabolism, Arabidopsis thaliana, Auxins, binding capacity, Biochemistry, Biological Sciences, Botany, Bryopsida, Crystallography, X-Ray, F box proteins, F-box protein, F-Box Proteins - agonists, F-Box Proteins - antagonists & inhibitors, F-Box Proteins - metabolism, Gene expression, Genes, hormonal regulation, Hormones, Hypocotyls, indole acetic acid, Indoleacetic Acids - metabolism, Insulin antibodies, Molecular probes, Molecules, mosses and liverworts, Physcomitrella patens, Plants, Protein Binding, Proteins, Receptors, Receptors, Cell Surface - agonists, Receptors, Cell Surface - antagonists & inhibitors, Receptors, Cell Surface - metabolism, Signal Transduction, Substrate Specificity, ubiquitin-protein ligase, Ubiquitination, Ubiquitins, X-ray diffraction