Phone: 024 765 22461
Warwick Centres and GRPs
Vacancies and Opportunities
For PhD and postdoctoral opportunities, and interest in potential collaborations, please contact me at the above email address.
Clathrin-mediated endocytosis allows cells to capture nutrients and other important molecules by engulfing them in a capsule made from the plasma membrane. This is a vital process that contributes not only to nutrient uptake but to other cellular functions including recycling of synaptic vesicles in the brain, communication within and between cells and development of cells and tissues to perform specialised functions. In addition the endocytic apparatus is used by some viruses (notably HIV and influenza) and bacteria to gain entry into cells and there is accumulating evidence that endocytic proteins are associated with a wide range of diseases including neurodegenerative disease and cancer.
Clathrin-mediated endocytosis operates through formation of a vesicle from the cell's membrane trapping cargo molecules inside. This process is controlled by a network of proteins which include clathrin and a set of adaptor proteins which bind to clathrin. Clathrin assembles to form a polyhedral cage which, together with its adaptor proteins, forms a coat around the vesicle. The vesicles then detach from the membrane and move to a location inside the cell to deliver their contents. It remains a mystery how so many different adaptor proteins coordinate with a single protein so that this cellular postal system can achieve its function.
We aim to solve this mystery using two main approaches. First, by using electron microscopy images of frozen protein mixtures we can determine three-dimensional maps that show what these proteins look like and how clathrin’s adaptor protein binding partners are arranged within a cage structure. Secondly, by using advanced biophysical techniques we can measure how these adaptor proteins bind to clathrin and how clathrin cage assembly and disassembly is controlled. In this way we hope determine how clathrin coats specify and are involved in so many critical functions in cells.
Research: Technical Summary
My current research focusses on understanding the structure and function of large multi-molecular systems, with the remarkable geometric assemblies formed by clathrin at the heart of this. The functions performed by clathrin are important not only for enabling selective uptake of molecules into cells but also because the machinery of endocytosis supports diverse functions vital to the health of an organism, and yet is exploited by pathogens to gain entry into cells.
Receptor-mediated endocytosis allows a cell to choose and absorb the substances it requires. During clathrin-mediated endocytosis a clathrin-coated vesicle is formed which contains only specifically selected cargo. The clathrin coat is central to the ability of the vesicle to choose its contents and requires that clathrin coordinates binding to a large number of adaptor protein partners. There are too many adaptor proteins to be able to bind all at once to clathrin so a process of selection must take place that will determine what is included in the vesicle and control the timing of internalisation. To understand how this works we are using structural biology and biophysics techniques to gain a three dimensional picture of clathrin cages bound to adaptor proteins and to understand the dynamics of coated vesicle assembly and disassembly.
The techniques we use include single particle analysis of cryo-electron microscopy images for high resolution structure determination, fluorescence spectroscopy, light scattering, circular dichroism and stopped flow kinetics. For sample preparation we use multiple biochemical techniques including protein expression, purification using automated column chromatography and gel electrophoresis. Using these approaches we aim to understand the biochemical interactions that enable cells to respond to external events through the highly adaptable process of endocytosis.
For a full list of publications, see WRAP
- BSc (Hons) Biochemistry, University of Bristol 1988
- PhD University of Bristol 1992
- 2021 - Professor, University of Warwick
- 2016 - 2021 Reader, University of Warwick
- 2016 – 2017 Royal Society Leverhulme Trust Senior Research Fellow
- 2007 - 2016 Associate Professor, University of Warwick
- 2004 - 2007 Assistant Professor, University of Warwick
- 2002 - 2004 MRC Career Development Fellow, University of Warwick
- 1999 - 2002 Research associate and MRC Career Development Fellow, Birkbeck College
- 1995 – 1999 Research Associate, MRC Laboratory of Molecular Biology, Cambridge
- 1992 - 1995 Post-doctoral Research Associate, University of Bristol