Recent mapping of all physical interactions between proteins in a given cell has confirmed the notion that interactions between proteins are highly regulated and underpin all cellular processes. Researchers and technologists have been presented with a major challenge – how to ask specific questions of such complex systems especially when protein interactions change with time in a given cell and result in different end states.
For example when a human cell responds to stress, specific interactions between master regulatory proteins start to drive a recovery process or initiate a controlled commitment to cell death. This project aims to generate a generic technology for solving this problem – introducing synthetic switches into live cells that can ‘fine-tune’ protein interactions by remote control. This exciting approach should allow the investigator to programme changes in defined protein-protein interactions by the introduction of small interfering molecules engineered to be switched on and off by light of carefully selected wavelengths.
Figure 1. Cartoon depicting the use of azobenzene molecules to change the conformation of peptides and influence the fate of cells.
Changes in the structure of a small molecule are triggered by external light pulses inducing conformational rearrangements in the peptide backbone and hence alterations of the biological properties of the Intracellular Biophotonic Nanoswitch (IBN). IBNs are light-sensitive molecular structures linked to the short peptide sequences that recognize features on the surface of a target/molecule that has been targeted for switching. Conventional and novel methods for IBN delivery into live cells will allow patterning of the swiches into populations of cells.
Operating these IBNs by light will allow the researcher to pattern the activation of switches in such complex cell populations or to ‘programme’ the switching process in single cells – a step-forward in the technology of manipulating master regulators of discrete intracellular pathways. The exciting prospect looms of gaining programmable photonic control over normal physiology (directing stem cell differentiation, manipulating wound healing and delaying cell senescence), neoplasia (cancer biology of cell cycle checkpoint dysfunction and photonically-controlled therapeutics), constructed cell communities (light-directed tissue engineering) and molecular target identification (the search for new medicines and products).
Figure 2. NMR structure of a crosslinked peptide derived to the proapoptotic Bak protein bound to Bcl-xL (PDB: 2LP8).
• Robert J. Mart, Dilruba Meah and Rudolf K. Allemann, ChemBioChem, 17, 698–701 (2016). DOI:10.1002/cbic.201500469.
• Robert J. Mart, Rachel J. Errington, Catherine L. Watkins, Sally C. Chappell, Marie Wiltshire, Arwyn T. Jones, Paul J. Smith and Rudolf K. Allemann, Molecular Biosystems, 9, 2597-2603 (2013). DOI:10.1039/C3MB70246D.
• Piotr Wysoczanski, Robert J. Mart, E. Joel Loveridge, Chris Williams, Sara B.-M. Whittaker, Matthew P. Crump and Rudolf K. Allemann,
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