Understanding key interactions between lipid membranes and proteins and their role in cellular signalling
Name of applicant
Andreas Haahr Larsen
Amount
DKK 450,962
Year
2019
Type of grant
Internationalisation Fellowships
What?
The body contains around 30 trillion cells. Communication between them is therefore essential, and this is mediated, among other things, by proteins that can bind to cells and leave them again. These so-called peripheral proteins are therefore involved in signalling processes that controls a range of processes, e.g. blood coagulation and tumour suppression. Many of these peripheral proteins contains domains that are specialised in binding to the cell's lipid membrane, i.e. that work as "protein anchors". We study one of the most abundant of these protein anchoring modules, the C2 domain, and investigate how it binds to the cells.
Why?
We aim at obtaining a better understanding of the protein anchoring C2 domains. With this understanding we will be able to better manipulate either the protein or the lipid cell membranes, in particular when the signalling system is not working as it should. Malfunctioning of the signalling system, in which the C2 plays a central role, may lead to diseases such as haemophilia or cancer. Therefore, a better understanding and thereby control of the system is highly desirable. Moreover, a better fundamental understanding of the function of homologues protein modules across protein families is valuable for further development in the field.
How?
We use computer simulations to obtain a detailed understanding of the binding and unbinding of C2 domains to cell membranes. Decades of rapid progress in software and hardware development has allowed for precise predictions to be made by such simulations. Therefore, today they can be used to obtain a detailed understanding of binding events, including binding orientation, binding strength, and lipid selectivity of the C2 domains. The simulations will be used symbiotically with experiments, as the simulations give dynamic and detailed understanding of experimental findings, and can be further used to generate hypothesis for new experimental studies. The research is conducted in the Sansom group at University of Oxford, which is among the world-leading groups for protein-lipid interactions.