Periodic Reporting for period 4 - CODE (Coincidence detection of proteins and lipids in regulation of cellular membrane dynamics)
Okres sprawozdawczy: 2023-07-01 do 2024-12-31
An overarching principle in the biology of eukaryotic cells is that distinct proteins and lipids localise to distinct cellular membranes to perform compartment‐specific functions. A long‐standing question has been how such specific localisation is achieved. In the CODE project we have investigated the hypothesis that coincidence detection of proteins and lipids is a major mechanism to achieve specificity in cytosol‐to-membrane recruitment of proteins and their complexes.
We have used mathematical modelling to model molecular kinetics of coincidence detection and predicted the relationship between coincidence detection and protein localisation, and we have investigated coincidence detection of the membrane lipid phosphatidylinositol 3‐phosphate (PI3P) and various proteins as a paradigm for how coincidence detection controls protein localisation, membrane contact site formation, and membrane dynamics. We have screened for new coincidence detectors using bioinformatics, quantitative proteomics and molecular biology approaches. These coincidence detectors have been functionally characterized in cell culture and model organisms and found to control cancer cell invasion, cancer cell nutrition, genome stability and other biologically relevant mechanisms. Their pharmacological inhibition might offer new therapeutic strategies in cancer. Results have been presented at international scientific conferences and leading scientific journals (including Nature Cell Biology, Cell Research, Nature Communications and EMBO Journal) and have been popularized online on web pages, social media and in popular-scientific magazines.
We have proven that coincidence detection is an important principle in recruitment of proteins to biological membranes, and that it plays a major role in diverse cellular processes, including cancer cell invasion, cancer cell nutrition, and maintenance of genome stability.