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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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Autores principales: Hirano, Ken-ichi, Suganami, Akiko, Tamura, Yutaka, Yagita, Hideo, Habu, Sonoko, Kitagawa, Motoo, Sato, Takehito, Hozumi, Katsuto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986876/
https://www.ncbi.nlm.nih.gov/pubmed/31934853
http://dx.doi.org/10.7554/eLife.50979
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author Hirano, Ken-ichi
Suganami, Akiko
Tamura, Yutaka
Yagita, Hideo
Habu, Sonoko
Kitagawa, Motoo
Sato, Takehito
Hozumi, Katsuto
author_facet Hirano, Ken-ichi
Suganami, Akiko
Tamura, Yutaka
Yagita, Hideo
Habu, Sonoko
Kitagawa, Motoo
Sato, Takehito
Hozumi, Katsuto
author_sort Hirano, Ken-ichi
collection PubMed
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.
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spelling pubmed-69868762020-01-30 Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice Hirano, Ken-ichi Suganami, Akiko Tamura, Yutaka Yagita, Hideo Habu, Sonoko Kitagawa, Motoo Sato, Takehito Hozumi, Katsuto eLife Developmental Biology 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. eLife Sciences Publications, Ltd 2020-01-16 /pmc/articles/PMC6986876/ /pubmed/31934853 http://dx.doi.org/10.7554/eLife.50979 Text en © 2020, Hirano et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Hirano, Ken-ichi
Suganami, Akiko
Tamura, Yutaka
Yagita, Hideo
Habu, Sonoko
Kitagawa, Motoo
Sato, Takehito
Hozumi, Katsuto
Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice
title 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_short 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
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986876/
https://www.ncbi.nlm.nih.gov/pubmed/31934853
http://dx.doi.org/10.7554/eLife.50979
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