Making small talk: Using chemistry to send messages across cell membranes

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The membrane is a barrier that prevents external chemicals from entering cells. So to communicate with the world around them, cells use multinanometre-long "nanodevices" in their membranes. These "nanodevices", G-protein-coupled receptors (GPCRs), are a class of transmembrane protein that mediates signal transduction (communication) by the cell, a crucial task that makes them key targets for medicinal chemistry. GPCRs transmit a signal when an external ligand binds to their exterior, which induces conformational changes in the transmembrane domains, then triggers the release of a message within the cell (via an enzymatic cascade). The development of completely artificial molecules that can transmit messages across membranes would lead to many exciting opportunities (see Nature Chemistry editorial: "Sending a message to the other side" http://www.nature.com/articles/nchem.2776). These include a new type of synthetic biology where new signalling pathways might 'short-circuit' natural signalling networks, making cells sensitive to unusual stimuli. We have shown that foldamers (folded oligomers) composed of aminoisobutyric acid (Aib) have particular promise for artificial signal transduction. These oligomers, which fold into helices, have an elongated shape that is very sensitive to binding events at their N-terminus, allowing binding information can be relayed over several nanometres.1 We have used this helical relay to create light-switchable Aib foldamers able to transmit photochemical information deep into membranes, in a manner reminiscent of rhodopsin.2 Most recently we developed a foldamer that transmitted binding information from an external ligand (Leu enkephalin) several nanometres into a membrane.3 In this project, we will apply this exciting class of molecule in a cellular context. Aib foldamers that bear new fluorescent reporter groups will be chemically synthesised, which will be followed by studies of their conformation and helicity switching in the membranes of vesicles and living cells. The signalling mechanism will be then linked to enzymatic activity, with a series of proteases and esterases used to transform non-binding or non-active signals into signalling molecules. If successful, this project would produce for the first time artificial communication between exterior catalytic reactions and the interior of living cells.This project will combine three areas with distinct skillsets, namely cell biology, industrial biotechnology and synthetic chemistry, adding interdisciplinary training to core skills in the latter two areas. It aligns with the BBSRC's "New strategic approaches to Industrial Biotechnology" especially "Innovative approaches to develop new biocatalytic entities and pathways"; we aim to develop synthetic cell signalling pathways that interface with biocatalysis. Project training will fulfil several BBSRC enabling themes, especially "new ways of working". References: [1] Brown, R. A.; Diemer, V.; Webb, S. J.; Clayden, J. Nature Chem. 2013, 5, 853. [2] De Poli, M.; Zawodny, W.; Quinonero, O.; Lorch, M.; Webb, S.J.; Clayden, J. Science 2016, 352, 575. [3] Lister, F. G. A.; Le Bailly, B. A. F.; Webb, S. J.; Clayden, J. Nature Chem. 2017, 9, 420.