Pinpointed Stimulation of EphA2 Receptors via DNA-Templated Oligovalence
- DNA nanostructures enable the attachment of functional molecules to nearly any unique location on their underlying structure. Due to their single-base-pair structural resolution, several ligands can be spatially arranged and closely controlled according to the geometry of their desired target, resulting in optimized binding and/or signaling interactions. Here, the efficacy of SWL, an ephrin-mimicking peptide that binds specifically to EphrinA2 (EphA2) receptors, increased by presenting up to three of these peptides on small DNA nanostructures in an oligovalent manner. Ephrin signaling pathways play crucial roles in tumor development and progression. Moreover, Eph receptors are potential targets in cancer diagnosis and treatment. Here, the quantitative impact of SWL valency on binding, phosphorylation (key player for activation) and phenotype regulation in EphA2-expressing prostate cancer cells was demonstrated. EphA2 phosphorylation was significantly increased by DNA trimers carrying three SWL peptides compared to monovalent SWL. InDNA nanostructures enable the attachment of functional molecules to nearly any unique location on their underlying structure. Due to their single-base-pair structural resolution, several ligands can be spatially arranged and closely controlled according to the geometry of their desired target, resulting in optimized binding and/or signaling interactions. Here, the efficacy of SWL, an ephrin-mimicking peptide that binds specifically to EphrinA2 (EphA2) receptors, increased by presenting up to three of these peptides on small DNA nanostructures in an oligovalent manner. Ephrin signaling pathways play crucial roles in tumor development and progression. Moreover, Eph receptors are potential targets in cancer diagnosis and treatment. Here, the quantitative impact of SWL valency on binding, phosphorylation (key player for activation) and phenotype regulation in EphA2-expressing prostate cancer cells was demonstrated. EphA2 phosphorylation was significantly increased by DNA trimers carrying three SWL peptides compared to monovalent SWL. In comparison to one of EphA2’s natural ligands ephrin-A1, which is known to bind promiscuously to multiple receptors, pinpointed targeting of EphA2 by oligovalent DNA-SWL constructs showed enhanced cell retraction. Overall, we show that DNA scaffolds can increase the potency of weak signaling peptides through oligovalent presentation and serve as potential tools for examination of complex signaling pathways.…
Verfasserangaben: | Christin MöserORCiD, Jessica S. LorenzORCiD, Martin SajfutdinowGND, David M. SmithORCiD |
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DOI: | https://doi.org/10.3390/ijms19113482 |
ISSN: | 1422-0067 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/30404153 |
Titel des übergeordneten Werks (Englisch): | International journal of molecular sciences |
Verlag: | MDPI |
Verlagsort: | Basel |
Publikationstyp: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Datum der Erstveröffentlichung: | 06.11.2018 |
Erscheinungsjahr: | 2018 |
Datum der Freischaltung: | 08.07.2021 |
Freies Schlagwort / Tag: | DNA nanostructure; EphA2; PC-3 cells; SWL; ephrin; multivalence |
Band: | 19 |
Ausgabe: | 11 |
Seitenanzahl: | 19 |
Fördernde Institution: | Fraunhofer Attract funding [601683]; European Regional Development FundEuropean Union (EU) [100185665]; University of Leipzig within the program of Open Access Publishing |
Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
DDC-Klassifikation: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Peer Review: | Referiert |
Publikationsweg: | Open Access / Gold Open-Access |
DOAJ gelistet |