Soluble and multivalent Jag1 DNA origami nanopatterns activate Notch without pulling force

Ioanna Smyrlaki, Ferenc Fördős, Iris Rocamonde-Lago, Yang Wang, Boxuan Shen, Antonio Lentini, Vincent C. Luca, Björn Reinius, Ana I. Teixeira and Björn Högberg ()
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Ioanna Smyrlaki: Karolinska Institutet
Ferenc Fördős: Karolinska Institutet
Iris Rocamonde-Lago: Karolinska Institutet
Yang Wang: Karolinska Institutet
Boxuan Shen: Karolinska Institutet
Antonio Lentini: Karolinska Institutet
Vincent C. Luca: Moffitt Cancer Center
Björn Reinius: Karolinska Institutet
Ana I. Teixeira: Karolinska Institutet
Björn Högberg: Karolinska Institutet

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The Notch signaling pathway has fundamental roles in embryonic development and in the nervous system. The current model of receptor activation involves initiation via a force-induced conformational change. Here, we define conditions that reveal pulling force-independent Notch activation using soluble multivalent constructs. We treat neuroepithelial stem-like cells with molecularly precise ligand nanopatterns displayed from solution using DNA origami. Notch signaling follows with clusters of Jag1, and with chimeric structures where most Jag1 proteins are replaced by other binders not targeting Notch. Our data rule out several confounding factors and suggest a model where Jag1 activates Notch upon prolonged binding without appearing to need a pulling force. These findings reveal a distinct mode of activation of Notch and lay the foundation for the development of soluble agonists.

Date: 2024
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DOI: 10.1038/s41467-023-44059-4

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