Observing proteins from birth to breakdown

He is one of the pioneers of a technique that makes it possible to observe cellular structures in molecular detail. And now Friedrich Förster, recently appointed Professor of Cryo-Electron Microscopy at Utrecht University, has been awarded a prestigious ERC Consolidator Grant. He will use the grant to study the workings of the endoplasmic reticulum, the compartment of the cell that specializes in the production of proteins. In so doing, he hopes to discover why the production of these proteins occasionally malfunctions, a situation occurring in many diseases.

Förster uses cryo-electron tomography (CET), a method that is similar to a CT scan, but used on cells that have been cryogenically frozen. This technique allows him to create three-dimensional images of macromolecules. “The main benefit of this method is that you don’t have to isolate the proteins that you want to study, as is the case in many other techniques”, he explains. “We observe them in their native surroundings, in almost life-like conditions.” CET makes it possible to observe the entire process of protein formation, from the ‘birth’ of the proteins, to the way they fold, how sugar groups bind to them, and eventually how they are broken down when defective or no longer needed.

Resolution revolution

The resolution of this imaging technology has dramatically improved over the past few years. Förster: “Around three years ago, there was a revolution when a direct detection method became available. Images that had contained low amounts of signal before suddenly became much clearer.” With his background as a physicist, Förster is always working to improve the technique. At Utrecht University, he now has access to one of the newest, most advanced CET microscopes in the local facility ‘EM square’. 

He came to Utrecht from Germany, where he studied in Aachen, then earned his PhD and worked at the Max Planck Institute for Biochemistry in Munich, specifically to work with the university’s equipment. He is working at the Bijvoet Center for Biomolecular Research since last summer. Förster: “Here in Utrecht, I can work together with other groups who do a lot of structural biology research. Plus, they do extremely high-level research on membrane-bound proteins here.”

Implications in diseases

Around one third of the production of proteins occurs at the endoplasmic reticulum (ER). Many diseases are tied to mistakes that start there. For example, proteins can be folded incorrectly, or problems can occur in the process of binding to sugar groups, called glycosylation. We know that the ER is involved in the disease cystic fibrosis, and there are implications that part of the problem behind various neurodegenerative diseases like Alzheimer’s lies in the ER. Förster hopes that his research, which has just received more than two million Euros in funding as part of the ERC Grant, will be able to contribute to a greater understanding of the causes of these diseases.