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Unlocking the Role of Lipids in the Activation Mechanism of the Epidermal Growth Factor Receptor (EGFR)

Principal Investigator: Ilpo Vattulainen, Department of Physics, Tampere University of Technology (Finland)
HPC Platform: Hermit of HLRS
HLRS Project ID: PP12071362

SUGARS CRITICALLY REGULATE GROWTH FACTOR, RECEPTOR STRUCTURE, AND FUNCTION IN MEMBRANES

“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 on HPC system Hermit of HLRS together with biochemical experiments to show for EGFR that receptor conformation depends in a critical manner on its glycosylation.

Glycosylated epidermal growth factor receptor (EGFR) in a lipid membrane. Glycans attached to glycosylation sites on the extracellular (upper) side of the membrane are rendered as stick models with transparent surfaces.Glycosylated epidermal growth factor receptor (EGFR) in a lipid membrane. Glycans attached to glycosylation sites on the extracellular (upper) side of the membrane are rendered as stick models with transparent surfaces.
Copyright: Jyrki Hokkanen at CSC – IT Center for Science (Espoo, Finland)

"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.

This project was published in PNAS (Proceedings of the National Academy of Sciences of the United States of Amerika). Link to the article: http://www.pnas.org/content/112/14/4334.full

Acknowledgments:
The simulations were carried out using the supercomputer Hermit of HLRS 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.

References:
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

About EGFR: Epidermal growth factor receptor (EGFR) is a membrane glycoprotein composed of an extracellular ligand binding domain, a single helical transmembrane segment, and an intracellular domain with kinase activity. It is considered as one of the most important membrane receptors, since a major fraction of drug development is targeted to EGFR, with an objective to alter its activity. This is largely due to the fact that EGFR-mediated signaling pathways regulate, e.g., cell proliferation and differentiation, which implies that uncontrolled activation of EGFR is often linked to emergence of diseases such as breast and lung tumors. In essence, EGFR is one of the important targets for cancer therapies.

Scientific Contact:
Ilpo Vattulainen, Prof., Dr. Tech
Department of Physics, Tampere University of Technology (Finland)
Email: ilpo.vattulainen@tut.fi

April 2015