Abstract
Signal transduction across phospholipid bilayer is an important process in biology that allows cells to respond to changes in their external environment and communicate among cells. Trans-bilayer signal transduction by sophisticated membrane proteins such as G-protein coupled receptors (GPCR) play crucial role in regulating key physiological processes. Being able to mimic the signal transduction by GPCRs has enormous opportunity in synthetic biology for potential application in artificial tissue signaling, biosensing and controlled drug delivery. In a general sense, GPCRs consist of a dynamically reconfigurable, hydrophilic-hydrophobic-hydrophilic (Hi-Ho-Hi) molecular structure where the hydrophobic part is buried in the lipid bilayer while the two hydrophilic ends remain on the two sides of the bilayer. In this research, we mimic the Hi-Ho-Hi molecular design principle of GPCRs to create a DNA-based transmembrane Nano-Sensor (TraNS) that dynamically reconfigures upon sensing a membrane-enclosed nucleic acid target. Four interwoven DNA strands are self-assembled to form each TraNS device. Two hydrophobic cholesterol anchors are covalently conjugated to create a hydrophobic belt around each TraNS device to help it to span the lipid bilayer, similar to the Hi-Ho-Hi nature of GPCRs. We design the TraNS device such that after insertion to lipid bilayer, it selectively switches from a closed to an open state upon sensing a nucleic acid target encapsulated inside the membrane. Gel electrophoresis and fluorescence spectra confirms the formation and configurational switch of the TraNS device. Next, we demonstrate the use of the TraNS device for biosensing application by detecting presence of non-small cell lung cancer specific micro-RNA: miR-21-5p in exosomes. We believe this is the first demonstration of mimic of a transmembrane signal transducing protein using DNA nanostructures and use of the nanostructure towards diagnostic application.
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