Research Groups

Research

Protein aided membrane remodeling and scission

Figure 1. Based on the structures observed by cryo electron microscopy, a molecular model of the co-polymer formed by the ESCRT-III members CHMP2A (gold) and CHMP3 (blue). Schematic representation of how a CHMP2-3 copolymer grows to form a protein dome (red) at the neck region of a budding membrane (yellow) which may lead to membrane neck narrowing and finally scission.

Cellular processes such as cytokinesis, the budding of enveloped retrovirus (e.g. HIV-1), and multivesicular biogenesis have direct links to human diseases including carcinogenesis and neuro-degeration. While seemingly unrelated, all of these involve membrane abscission for generating two newly formed membrane bound structures - a process aided by the cytosolic proteins called the ESCRT-III.

We are interested in how ESCRTs and lipids interact to shape these highly dynamic membrane systems. This requires us to quantitatively understand how these complex interactions occur, the lipido-protein structures that are produced, and the mechanics of membrane scission in the native conditions. In order to achieve this, we will reconstitute select sub-systems in bio-mimetic environments and investigate them under defined conditions by using a combination of existing technologies and in-house custom-made tools. To understand ESCRT mediated membrane remodeling and scission, targeted structural and biophysical studies will be driven by our ability to produce functional recombinant ESCRTs and to label them with a variety of different probes. Our specific research tools and interests within this quest are the following:

• For understanding the dynamics of ESCRT-III assembly on membranes we will use solid supported bilayers and study the processes in real time using surface sensitive label free and fluorescence detection simultaneously.
• To follow the structures, composition and direction of growth of ESCRT-III assemblies as they mature on lipid membranes we will develop novel probes and use cryo electron microscopy.
• Since ESCRT-III polymer must form through the central pore of a membrane tubule, thereby posing steric hindrance for scission, we wish to study how pore closure followed by scission takes place. To that effect we will use membrane nano-tubes drawn from black lipid membranes and measure their ionic permeability as a sensitive read out for pore closure and simultaneously follow the ESCRT-III assembly using fluorescence microscopy with single dye sensitivity.

Whenever possible, our ambition is to test the model/hypotheses arising from in vitro data in living systems and in silico. We hope to use the lessons learned for therapeutic intervention as well as bionanotechnological applications.

Recent publications

Bhagawati, M., Lata, S., Tampe R., Piehler J., In situ light controlled targeting of proteins into functional micropatterns. J. Am. Chem. Soc. 132 (2010) 5932-3.

Fabrikant G., Lata S., Riches J.D., Briggs J.A.G.,Weissenhorn, W., Kozlov, M.M., Mechanism of membrane fission by ESCRT-III assemblies formed by CHMP2-CHMP3. Plos Comp Biol 5 (2009): e1000575.

Lata S., Schoehn, G., Jain, A., Pires, R., Piehler, J., Gottlinger H.G., Weissenhorn W., Helical structures of ESCRT-III are disassembled by VPS4, Science 321 (2008) 1354-57.

Gavutis M.*, Lata S.*, Lamken P., Mueller P., Piehler J., Lateral ligand-receptor interactions on membranes studied by simultaneous fluorescence-interference detection, Biophys. J. 88 (2005) 4289-4302.

View all publications listed on the University of Bristol's publication database