Sugars critically regulate growth factor receptor structure and function in membranesComputational biophysics at TUT has shown that the conformation and therefore also the function of cell membrane receptors can depend in a critical manner on receptor glycosylation.
“Our findings are an important step towards a better understanding of receptor structure and function in cell membranes“, says Prof. Ilpo Vattulainen from Tampere University of Technology.
Communication between the outside and the inside of a cell takes place to a large extent through cell membrane receptors. Once activated by specific ligands, the receptors relay the signals that regulate critical cellular events, such as cell division in case of the human epidermal growth factor receptor (EGFR). Misregulation of this signaling process, for instance by receptor mutations, can lead to the development and progression of epithelial cancers, i.e. lung cancer. For these reasons, EFGR is an important target for anticancer therapies. Despite its critical role in cell division and targeted anticancer therapies, little is known about the structure of the complete EGFR in biological membranes.
Scientists at Tampere University of Technology, Paul Langerhans Institute, and Max Planck Institute for Molecular Cell Biology and Genetics in Dresden have shown the profound importance of glycosylation in membrane receptor conformation. Glycosylation stands for an array of complex carbohydrates bound to specific sites of the receptor that face to the outside of cells. The researchers used extensive atomistic simulations together with biochemical experiments to show for EGFR that receptor conformation depends in a critical manner on its glycosylation.
"We hope that our achievements will help other scientists to develop better drugs and antibodies for anticancer therapies", says Prof. Ilpo Vattulainen.
"The discovery we made would not have been possible without the close interplay between molecular simulations and biochemical experiments. This kind of truly interdisciplinary collaboration is definitely the approach of choice to clarify challenging questions in biomedical research", adds Dr. Coskun from the Paul Langerhans Institute in Dresden.
N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes. K. Kaszuba, M. Grzybek, A. Orlowski, R. Danne, T. Rog, K. Simons, Ü. Coskun, and I. Vattulainen. Proceedings of the National Academy of Sciences USA 112, 4334-4339 (2015); doi: 10.1073/pnas.1503262112
Link to the article: http://www.pnas.org/content/112/14/4334.full
Prof. Ilpo Vattulainen
Department of Physics, Tampere University of Technology
Phone: +358 400 510 592
The simulations were carried out using the supercomputers at Hermit (High Performance Computing Center Stuttgart (HLRS), Germany) through resources granted by PRACE (Partnership for Advanced Computing in Europe), and with resources awarded by CSC — IT Center for Science Ltd (Espoo, Finland). The research was carried out by support granted by the European Research Council (Advanced Grant project CROWDED-PRO-LIPIDS) and the Academy of Finland through its Center of Excellence Program.