Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice
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 o...
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doaj-f11b723230544f3da5dc4682c7db396b2021-05-05T20:44:43ZengeLife Sciences Publications LtdeLife2050-084X2020-01-01910.7554/eLife.50979Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in miceKen-ichi Hirano0Akiko Suganami1Yutaka Tamura2Hideo Yagita3Sonoko Habu4Motoo Kitagawa5Takehito Sato6Katsuto Hozumi7https://orcid.org/0000-0002-7685-6927Department of Immunology, Tokai University School of Medicine, Isehara, JapanDepartment of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba, JapanDepartment of Immunology, Juntendo University School of Medicine, Tokyo, JapanDepartment of Immunology, Juntendo University School of Medicine, Tokyo, JapanDepartment of Biochemistry, International University of Health and Welfare School of Medicine, Narita, JapanDepartment of Immunology, Tokai University School of Medicine, Isehara, JapanDepartment of Immunology, Tokai University School of Medicine, Isehara, JapanDelta-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.https://elifesciences.org/articles/50979notch ligandDll4Dll1T cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ken-ichi Hirano Akiko Suganami Yutaka Tamura Hideo Yagita Sonoko Habu Motoo Kitagawa Takehito Sato Katsuto Hozumi |
spellingShingle |
Ken-ichi Hirano Akiko Suganami Yutaka Tamura Hideo Yagita Sonoko Habu Motoo Kitagawa Takehito Sato Katsuto Hozumi Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice eLife notch ligand Dll4 Dll1 T cells |
author_facet |
Ken-ichi Hirano Akiko Suganami Yutaka Tamura Hideo Yagita Sonoko Habu Motoo Kitagawa Takehito Sato Katsuto Hozumi |
author_sort |
Ken-ichi Hirano |
title |
Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice |
title_short |
Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice |
title_full |
Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice |
title_fullStr |
Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice |
title_full_unstemmed |
Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice |
title_sort |
delta-like 1 and delta-like 4 differently require their extracellular domains for triggering notch signaling in mice |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2020-01-01 |
description |
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. |
topic |
notch ligand Dll4 Dll1 T cells |
url |
https://elifesciences.org/articles/50979 |
work_keys_str_mv |
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