A non-B DNA binding peptidomimetic channel alters cellular functions

Raj Paul, Debasish Dutta, Titas Kumar Mukhopadhyay, Diana Müller, Binayak Lala, Ayan Datta, Harald Schwalbe and Jyotirmayee Dash ()
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Raj Paul: Indian Association for the Cultivation of Science
Debasish Dutta: Indian Association for the Cultivation of Science
Titas Kumar Mukhopadhyay: Indian Association for the Cultivation of Science
Diana Müller: Center for Biomolecular Magnetic Resonance (BMRZ), Goethe, University Frankfurt, Max-von-Laue Strasse 7
Binayak Lala: Indian Association for the Cultivation of Science
Ayan Datta: Indian Association for the Cultivation of Science
Harald Schwalbe: Center for Biomolecular Magnetic Resonance (BMRZ), Goethe, University Frankfurt, Max-von-Laue Strasse 7
Jyotirmayee Dash: Indian Association for the Cultivation of Science

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

Abstract: Abstract DNA binding transcription factors possess the ability to interact with lipid membranes to construct ion-permeable pathways. Herein, we present a thiazole-based DNA binding peptide mimic TBP2, which forms transmembrane ion channels, impacting cellular ion concentration and consequently stabilizing G-quadruplex DNA structures. TBP2 self-assembles into nanostructures, e.g., vesicles and nanofibers and facilitates the transportation of Na+ and K+ across lipid membranes with high conductance (~0.6 nS). Moreover, TBP2 exhibits increased fluorescence when incorporated into the membrane or in cellular nuclei. Monomeric TBP2 can enter the lipid membrane and localize to the nuclei of cancer cells. The coordinated process of time-dependent membrane or nuclear localization of TBP2, combined with elevated intracellular cation levels and direct G-quadruplex (G4) interaction, synergistically promotes formation and stability of G4 structures, triggering cancer cell death. This study introduces a platform to mimic and control intricate biological functions, leading to the discovery of innovative therapeutic approaches.

Date: 2024
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DOI: 10.1038/s41467-024-49534-0

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