Entirely Artificial Signal Transduction with a Primary Messenger

Bernitzki, Kai; Schräder, Thomas

doi:10.1002/ange.200902973

Cited by 15 publications

(6 citation statements)

References 37 publications

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“…21−23 For example, the Schrader group synthesized receptor analogue compounds to mimic the signal transduction mechanism of ligand-induced receptor dimerization and the release of secondary messengers. 22,24 Another notable design was reported by Hunter et al, who synthesized a pH-sensitive transducer with controlled translocation to transmit a chemical signal across the membrane, triggering signal amplification inside the cell and even releasing molecules outside the cell. 21,23,25,26 Although these excellent artificial systems have been reported, it remains necessary to develop smarter, more predictable, and more precisely controlled artificial signal transduction systems.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Inspired by the “rules of life”, that is, understanding biology by building a new biology, building artificial cells from the bottom up would open up new avenues for a deep understanding of fundamental biological processes. , Moreover, reproducing biological processes has potential man-made applications, such as sensing, drug delivery, bio-engineering, and so on. − Recently, many efforts have been devoted to construct artificial signal transduction systems to mimic natural cell signaling processes. − The main challenge is the de novo design of such smart systems that could recognize the signal stimuli, translate the signal from the exterior to the interior of the cell, not simply physical transport across the membrane, and finally initiate cascade reactions inside the cell. Chemists have focused on creating new functional molecules acting as receptors to send and transform signals across the membrane. − For example, the Schrader group synthesized receptor analogue compounds to mimic the signal transduction mechanism of ligand-induced receptor dimerization and the release of secondary messengers. , Another notable design was reported by Hunter et al, who synthesized a pH-sensitive transducer with controlled translocation to transmit a chemical signal across the membrane, triggering signal amplification inside the cell and even releasing molecules outside the cell. ,,, Although these excellent artificial systems have been reported, it remains necessary to develop smarter, more predictable, and more precisely controlled artificial signal transduction systems.…”

Section: Introductionmentioning

confidence: 99%

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DNA-Based Artificial Signaling System Mimicking the Dimerization of Receptors for Signal Transduction and Amplification

et al. 2021

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Transmembrane signal transduction is of profound significance in many biological processes. The dimerization of cellsurface receptors is one prominent mechanism by which signals are transmitted across the membrane and trigger intracellular cascade amplification reactions. Recreating such processes in artificial systems has potential applications in sensing, drug delivery, bioengineering, and providing a new route for a deep understanding of fundamental biological processes. However, it remains a challenge to design artificial signal transduction systems working by the receptor dimerization mechanism in a predictable and smart manner. Here, benefitting from DNA with features of programmability, controllability, and flexible design, we use DNA as a building material to construct an artificial system mimicking dimerization of receptors for signal transduction and cascade amplification. DNAbased membrane-spanning receptor analogues are designed to recognize external signals, which drives two receptors into close spatial proximity to activate DNAzymes inside the cell-mimicking system. The activation of the DNAzyme initiates the catalyzed cleavage of encapsulated substrates and leads to the release of fluorescent second messengers for signal amplification. Such an artificial signal transduction system extends the range of biomimetic DNA-based signaling systems, providing a new avenue to study natural cell signaling processes and artificially regulate biological processes.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA-Based Artificial Signaling System Mimicking the Dimerization of Receptors for Signal Transduction and Amplification

et al. 2021

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“…2,3 Although numerous examples of synthetic membrane channels and transporters have been reported, 4-10 signal transduction without mass transfer is considerably more challenging. [11][12][13][14][15][16] We have recently reported a novel transmembrane signaling mechanism, which operates by controlled translocation of a synthetic transducer across a vesicle lipid bilayer (Figure 1). 17,18 The external recognition head group of the transducer becomes membrane permeable in response to an external chemical stimulus, which leads to membrane translocation, exposing a catalytic head group to the interior of the vesicle.…”

Section: Introductionmentioning

confidence: 99%

A Synthetic Vesicle-to-Vesicle Communication System

2019

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A molecular signal displayed on the external surface of one population of vesicles was used to trigger a catalytic process on the inside of a second population of vesicles. The key recognition event is the transfer of a protein (NeutrAvidin) bound to vesicles displaying desthiobiotin to vesicles displaying biotin. The desthiobiotin•protein complex was used to anchor a synthetic transducer in the outer leaflet of the vesicles, and when the protein was displaced, the transducer translocated across the bilayer to expose a catalytic head group to the internal vesicle solution. As a result, an ester substrate encapsulated on the inside of this second population of vesicles was hydrolysed to give a fluorescence output signal. The protein has four binding sites, which leads to multivalent interactions with membrane-anchored ligands and very high binding affinities. Thus biotin, which has a dissociation constant three orders of magnitude higher than desthiobiotin, did not displace the protein from the membrane-anchored transducer, and membrane-anchored biotin displayed on the surface of a second population of vesicles was required to generate an effective input signal. ASSOCIATED CONTENT Supporting Information Materials and methods, experimental details, synthetic procedures and compound characterization are available in the Supplementary Materials. This material is available free of charge via the Internet at http://pubs.acs.org.

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“…evoked proximity of the two transmembrane molecules and ensued dimerization of endofacial termini of these molecules, without compromising integrity of the lipid bilayer. Typical results in these studies included a release of a UV-active molecule 7 or an energy transfer event between the dimerizing "sub-units" 9 . Another class of bionic receptors was designed in recent years by Hunter et al [10][11][12] using molecules that exhibit controlled "bobber"-like translocation across the lipid bilayer.…”

mentioning

confidence: 99%

“…One class of bionic signalling receptors, initially designed by Hunter and Williams et al 7 8 and later adopted by Schrader et al 9 , relies on the toolbox of chemically induced dimerization and uses membrane-spanning cholesterol dimers. The dimerization event at the exo-surface (due to e.g.…”

mentioning

confidence: 99%

Transmembrane signalling by a bionic receptor: biological input and output, chemical mechanism of signal transduction

Løvschall¹,

Monge²,

Nielsen³

et al. 2021

Preprint

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Signal transduction through sealed biological membranes is among the most important evolutionary achievements. Herein, we focus on the development of artificial signal transduction mechanisms and engineer a bionic receptor with capacity of transduction of biological signals across biological membranes using tools of chemistry. The bionic receptor described in this work exhibits similarity with the natural counterpart in the most essential characteristics: in having an exofacial ligand for signal capture, in being membrane anchored, and in featuring a releasable secondary messenger molecule, which performs enzyme activation in the endo volume. The main difference with the natural receptors is that signal transduction across the lipid bilayer was performed using the tools of organic chemistry, namely a self-immolative linker. The highest novelty of our work is that the artificial signalling cascade designed herein achieved transmembrane activation of enzymatic activity, as is the hallmark of activity by natural signalling receptors.

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Entirely Artificial Signal Transduction with a Primary Messenger

Cited by 15 publications

References 37 publications

DNA-Based Artificial Signaling System Mimicking the Dimerization of Receptors for Signal Transduction and Amplification

DNA-Based Artificial Signaling System Mimicking the Dimerization of Receptors for Signal Transduction and Amplification

A Synthetic Vesicle-to-Vesicle Communication System

Transmembrane signalling by a bionic receptor: biological input and output, chemical mechanism of signal transduction

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