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

• Published in: Nature communications Vol. 15; no. 1; p. 465
• Main Authors: Smyrlaki, Ioanna, Fördős, Ferenc, Rocamonde-Lago, Iris, Wang, Yang, Shen, Boxuan, Lentini, Antonio, Luca, Vincent C., Reinius, Björn, Teixeira, Ana I., Högberg, Björn
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 147/28; 38/77; 45/29; 45/91; 631/61/350/2093; 631/80/86; 82/80; 96/100; 96/63; Binders; Calcium-Binding Proteins - metabolism; Deoxyribonucleic acid; DNA; Embryogenesis; Embryonic growth stage; Epidermal growth factor; Humanities and Social Sciences; Jagged-1 Protein - genetics; Jagged-1 Protein - metabolism; Ligands; Medicin och hälsovetenskap; multidisciplinary; Nervous system; Notch protein; Pneumatics; Proteins; Receptor mechanisms; Receptors; Receptors, Notch - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - physiology; Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44059-4

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. The Notch receptor is known to be activated by a pulling force, but whether it is strictly required remains to be clarified. Here, the authors demonstrate activation of Notch through soluble multivalent DNA origami constructs, showing effects in neuroepithelial-like stem cells.