Ubiquitin is found in almost all tissues and is involved in a wide variety of cellular processes, e.g., protein degradation, signal transduction and cell cycle control. The addition of ubiquitin alters the characteristics of proteins, including their half life, function or location. Prof. Dr. Martin Scheffner’s work is dedicated to the exploration of this versatile protein. The researcher from Konstanz studies the enzymes of the ubiquitin system and their role in human disease. In addition, in his role as the dean of the Faculty of Sciences, Scheffner is committed to the development of Konstanz University and its research.
Ubiquitin is a small protein found in all eukaryotic cells (from Latin ubique = everywhere or ubiquitous). The protein’s best-known role is probably its involvement in protein quality control by way of targeting wrongly folded or otherwise defective proteins for degradation via the proteasome. However, ubiquitin has many more functions. “The ubiquitin system is one of the most important regulatory systems in eukaryotic cells and involved in almost all cellular processes,” explained Martin Scheffner, professor of cellular biochemistry at the University of Konstanz.
The diversity of the ubiquitin system explains Scheffner’s fascination for the protein and is one of the major reasons why he has chosen to focus on this topic. “The number and function of the enzymes and substrates involved, the types of modifications and regulatory possibilities seem to be endless,” said Scheffner with great enthusiasm. However, at the start of his scientific career, Scheffner had no idea that he would end up doing research on ubiquitin. “As a general rule, discoveries cannot be planned,” he concluded. His interest in the molecular mechanisms that play a role in the pathogenesis of cancer developed when he did his PhD at the University of Konstanz.
He went on to do post-doctoral research at the National Cancer Institute in the USA (Bethesda, MD) where he investigated the carcinogenic properties of human papillomaviruses (HPV). Some HPV types can cause cervical cancer. During his research at the National Cancer Institute, he came into contact with the ubiquitin-proteasome (UPS) system and was able to show that a carcinogenic HPV protein uses the ubiquitin system in order to degrade and hence inactivate the tumour suppressor protein p53. “Back then, little was known about the ubiquitin-proteasome system and the enzymes involved. So I decided to concentrate on it,” Scheffner explained.
Due to its central role in many cellular processes, the deregulation of ubiquitin system components – for example the inactivation of an enzyme due to the presence of a mutation in the underlying gene – is associated with disturbances in cellular processes, which in turn contributes to the development of diseases such as cancer. And this is what Scheffner’s work is all about: “We are mainly interested in identifying proteins and cellular processes that are associated with the development of certain diseases,” Scheffner said. Although Scheffner’s team’s findings are primarily basic research, they can also contribute to the development of new therapeutic approaches. Scheffner’s team basically focusses on two areas. The first research area deals with changes in the biochemical properties of proteins resulting from the attachment of ubiquitin and ubiquitin-like proteins. The changes not only depend on the site where the protein is ubiquitinated, but also on whether one ubiquitin molecule or chains of ubiquitin molecules are added to the target protein, i.e. whether the protein is mono-, oligo- or polyubiquitinated. “For these investigations, we are working closely with a team of researchers led by Professor Andreas Marx from the Department of Chemistry at the University of Konstanz and we are using so-called unnatural amino acids for our investigations,” said Scheffner going on to point out that unnatural amino acids are used to synthesise defined ubiquitin chains in order to study the impact of specific ubiquitin side chains on the fate of the modified protein in biochemical terms.
The researchers’ second area of interest is specific ubiquitin ligases and their role in the development of human diseases. These enzymes recognise the target protein and cause the attachment of ubiquitin to a specific amino acid on the target protein. In other words, the enzymes are crucial for correct ubiquitination. “We are trying to gain insights into the cellular processes that lead to Angelman syndrome, a neurogenetic disorder characterised by intellectual and developmental disabilities,” Scheffner said. It is known that the ubiquitin ligase E6AP/UBE3A is involved in the pathogenesis of the disease; however, its role remains enigmatic. In a recent study, Scheffner reported on evidence for the potential involvement of E6AP, which had previously received little attention. “The results suggest an effect on the transcriptional level; however, the exact mechanism still needs to be clarified,” said Scheffner.
Prior to his current position, Martin Scheffner was already studying biology and he did his PhD thesis at the University of Konstanz. A matter of chance turned out to be a stroke of luck. “When I was a student, the biology courses at Konstanz University were already specifically focussed on molecular processes,” said Scheffner, who had no hesitation in returning to Konstanz as a professor in 2004. “For me, the University of Konstanz is a modern, research-oriented institution that makes a point of working across disciplinary borders.” In addition to being professor in the Department of Biology, Scheffner is also dean of the Faculty of Sciences and vice coordinator of the Konstanz Research School Chemical Biology. “This gives me the opportunity to shape the development of the University of Konstanz as a whole and the research priorities of our faculty specifically,” said Scheffner explaining his commitment. The Konstanz Research School Chemical Biology in particular provides Scheffner with insights into the research activities of his colleagues.
Scheffner is extremely happy to work at the University of Konstanz, and it is not surprising that he has never seriously considered a career in the industry. “In industry, research is always geared towards market conditions, which would not give me the freedom to decide on which projects I would like to carry out,” said Scheffner explaining why he opted for an academic career.
Prof. Dr. Martin Scheffner
Department of Cellular Biochemistry
University of Konstanz