AI Article Synopsis
- The Notch signaling pathway is crucial for determining cell fate and is influenced by the ubiquitin ligase Deltex.
- Using NMR spectroscopy, researchers identified how Deltex interacts with the Notch ankyrin (ANK) domain, highlighting the N-terminal WWE motif as the binding site.
- Mutations in either Deltex or ANK disrupt their interaction and the enhancement of Notch transcriptional activation, while an unexpected finding reveals that Deltex can still bind to the Notch intracellular domain without its WWE domain, indicating a potential secondary interaction.
Article Abstract
The Notch signaling pathway, an important cell fate determination pathway, is modulated by the ubiquitin ligase Deltex. Here, we investigate the structural basis for Deltex-Notch interaction. We used nuclear magnetic resonance (NMR) spectroscopy to assign the backbone of the Drosophila Deltex WWE domain and mapped the binding site of the Notch ankyrin (ANK) domain to the N-terminal WWE motif. Using cultured Drosophila S2R+ cells, we find that point substitutions within the ANK-binding surface of Deltex disrupt Deltex-mediated enhancement of Notch transcriptional activation and disrupt ANK binding in cells and in vitro. Likewise, ANK substitutions that disrupt Notch-Deltex heterodimer formation in vitro block disrupt Deltex-mediated stimulation of Notch transcription activation and diminish interaction with full-length Deltex in cells. Surprisingly, the Deltex-Notch intracellular domain (NICD) interaction is not disrupted by deletion of the Deltex WWE domain, suggesting a secondary Notch-Deltex interaction. These results show the importance of the WWE:ANK interaction in enhancing Notch signaling.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338078 | PMC |
| http://dx.doi.org/10.1016/j.str.2023.03.003 | DOI Listing |
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