Research in our lab aims to understand the molecular mechanisms and signalling pathways that control the distribution and dynamics of subcellular components, focusing on structure, function, molecular mechanism and regulation of the key biomolecular machines cytoskeletal polymers that establish, maintain, and adapt subcellular organisation. We also seek to apply that knowledge to develop novel chemical tools to manipulate these systems. We take a multi-disciplinary approach that combines advanced cell imaging with cell biology, biophysics and structural approaches to define the molecular basis of these dynamic processes.

Our first major contribution was to show, how a microtubule motor, kinesin-1, recognises the some of the cargo that it carries (Science, 2013, 10.1126/science.1234264). We have since gone onto show how cargo engagement can regulate the activity of the motor (PNAS, 2016, 10.1073/pnas.1520817113) and identified new cargo recognition mechanism (eLife, 2018, 10.7554/eLife.38362). Our recent work in this area employing computational structure prediction and electron microscopy has led to the development of a new model for the autoregulation of the kinesin-1 holoenzyme (Science Advances, 2022, 10.1126/sciadv.abp9660) and demonstrate a novel mechanism for binding to lipid membranes (Science Advances, 2021, 10.1126/sciadv.abg6636)

An important recent focus us now is to use this information to develop peptides and small molecules that can manipulate these cargo recognition and autoregulatory mechanisms and to understand whether such molecules may be of therapeutic use. These include the development of a compound that promotes kinesin-1 driving changes in cytoskeletal organisation (PNAS, 2017,10.1073/pnas.1715115115) and most recently, de novo designed cell penetrating peptides that target the kinesin to control its activity (Cell Chemical Biology 2021, 10.1016/j.chembiol.2021.03.010; Nature Chemical Biology 2022 , 10.1038/s41589-022-01076-6; Nature Chemical Biology 2024, 10.1038/s41589-024-01640-2).

In a related theme, we have begun to employ cryo-electron tomography as a tool to examine cytoskeletal ultrastructure, revealing for the first time, that some microtubules can contain actin filaments within their lumen (JCB, 2020, 10.1083/jcb.201911154 and Biorxiv, 2023, 10.1101/2023.11.24.568450v1). Ongoing work is focussed understanding the function of these new cytoskeletal composites in platelets and other cell types.