Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice
- Tokai University School of Medicine, Japan
- Chiba University, Japan
- Juntendo University School of Medicine, Japan
- International University of Health and Welfare School of Medicine, Japan
- Tokai University, Japan
Abstract
Delta-like (Dll) 1 and Dll4 differently function as Notch ligands in a context-dependent manner. As these ligands share structural properties, the molecular basis for their functional difference is poorly understood. Here, we investigated the superiority of Dll4 over Dll1 with respect to induction of T cell development using a domain-swapping approach in mice. The DOS motif, shared by Notch ligands—except Dll4—contributes to enhancing the activity of Dll for signal transduction. The module at the N-terminus of Notch ligand (MNNL) of Dll4 is inherently advantageous over Dll1. Molecular dynamic simulation revealed that the loop structure in MNNL domain of Dll1 contains unique proline residues with limited range of motion. The Dll4 mutant with Dll1-derived proline residues showed reduced activity. These results suggest that the loop structure—present within the MNNL domain—with a wide range of motion ensures the superiority of Dll4 and uniquely contributes to the triggering of Notch signaling.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4 and 6.
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X-ray crystal structure of Notch ligand Delta-like 1Protein Data Bank, 4XBM.
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Complex of Notch1 (EGF11-13) bound to Delta-like 4 (N-EGF2)Protein Data Bank, 4XLW.
Article and author information
Author details
Funding
Japan Society for the Promotion of Science (16K08848)
- Katsuto Hozumi
Ministry of Education, Culture, Sports, Science, and Technology (22021040)
- Katsuto Hozumi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tomohiro Kurosaki, Osaka University, Japan
Ethics
Animal experimentation: Animal experimentation: All animal experiments were performed under protocols approved by the Animal Experimentation Committee of Tokai University (Approval No.: 165015, 171002, 182026, 193040), which is further monitored by the Animal Experimentation Evaluation Committee of Tokai University with researcher for Humanities/Sociology and external expert.
Version history
- Received: August 9, 2019
- Accepted: January 9, 2020
- Accepted Manuscript published: January 14, 2020 (version 1)
- Accepted Manuscript updated: January 16, 2020 (version 2)
- Version of Record published: January 28, 2020 (version 3)
Copyright
© 2020, Hirano et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice
eLife 9:e50979.
https://doi.org/10.7554/eLife.50979
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