Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice

Abstract
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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.

The following previously published data sets were used

1. Kershaw NJ
2. Church NL
3. Griffin MDW
4. Luo CS
5. Adams TE
6. Burgess AW
(2015) X-ray crystal structure of Notch ligand Delta-like 1
Protein Data Bank, 4XBM.

https://www.rcsb.org/structure/4XBM
1. Luca VC
2. Jude KM
3. Pierce NW
4. Nachury MV
5. Fischer S
6. Garcia KC
(2015) Complex of Notch1 (EGF11-13) bound to Delta-like 4 (N-EGF2)
Protein Data Bank, 4XLW.

https://www.rcsb.org/structure/4XLW

Article and author information

Author details

Ken-ichi Hirano

Department of Immunology, Tokai University School of Medicine, Isehara, Japan

Competing interests
The authors declare that no competing interests exist.
Akiko Suganami

Department of Bioinformatics, Chiba University, Chiba, Japan

Competing interests
The authors declare that no competing interests exist.
Yutaka Tamura

Department of Bioinformatics, Chiba University, Chiba, Japan

Competing interests
The authors declare that no competing interests exist.
Hideo Yagita

Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Sonoko Habu

Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Motoo Kitagawa

Department of Biochemistry, International University of Health and Welfare School of Medicine, Narita, Japan

Competing interests
The authors declare that no competing interests exist.
Takehito Sato

Department of Immunology, Tokai University, Isehara, Japan

Competing interests
The authors declare that no competing interests exist.
Katsuto Hozumi

Department of Immunology, Tokai University, Isehara, Japan

For correspondence
hozumi@is.icc.u-tokai.ac.jp

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7685-6927

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.

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.

Copyright

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.