Ivan ĐIKIĆ and Brenda SCHULMAN
Winners of the 2023 Louis-Jeantet Prize for Medicine

Ivan ĐIKIĆ, of Croatian nationality, and Brenda SCHULMAN, of American nationality, will share the 2023 Louis-Jeantet Prize for Medicine for their contributions to our understanding of the functions of ubiquitin and the mechanisms of ubiquitination.

Born in 1966, Ivan Đikić was trained as a medical doctor in Zagreb and pursued his PhD at New York University. He established his first independent group at the Ludwig Institute for Cancer Research in Uppsala, before moving to the Goethe University Frankfurt, where he was recruited as Professor of Biochemistry. Since 2009, Đikić has led the Institute of Biochemistry II at Goethe University as Director. He was also a founding Director of the Buchmann Institute for Molecular Life Sciences from 2009 to 2013. In 2018, Đikić was appointed as a Fellow of the Max Planck Institute of Biophysics in Frankfurt.

Born in 1967, Brenda Schulman obtained her Bachelor’s degree from the Johns Hopkins University and her PhD from MIT. She carried out her postdoctoral work at Massachusetts General Hospital and Memorial Sloan-Kettering before starting her independent career at St. Jude Children’s Research Hospital. From 2005 to 2017, she was a Howard Hughes Medical Institute Investigator. In 2016, she was recruited as a Director at the Max Planck Institute of Biochemistry in Martinsried, Germany, where she heads the Department of Molecular Machines and Signaling. She is also an Honorary Professor at Technical University of Munich.

Both Ivan Đikić and Brenda Schulman are elected members of the German National Academy of Sciences Leopoldina, the European Molecular Biology Organization (EMBO) and the American Academy of Arts and Sciences. They have received numerous prizes, including, by Đikić, the Sir Hans Krebs Prize, the German Cancer Award, and the William C. Rose Award, and by Schulman, the US Presidential Early Career Award for Scientists and Engineers, and election to the National Academy of Sciences (USA). They both received the Gottfried Wilhelm Leibniz Prize and the Ernst Jung Prize for Medicine.

Ubiquitin: a protein with many faces and functions

To function properly, cells rely on thousands of different proteins to perform their jobs, which must be degraded and recycled after completing their task. Proteins are labelled for degradation by the attachment of ubiquitin in a process known as ubiquitination, which is performed by a family of proteins called E3 ligases. There are hundreds of different E3 ligases, allowing for tremendous diversity and substrate specificity. The deregulation of this process is frequently associated with the development and progression of human pathologies and diseases, in particular neurodegenerative diseases. In recent years, we have witnessed a great deal of interest around ubiquitin, opening many new avenues for the development of novel therapies.

The complementary research of Brenda Schulman and Ivan Đikić highlights the importance of scientific co-operation to better understand complex biological processes. Schulman investigates how E3 ligases are structured, operated, and controlled. She seeks to understand how ubiquitination is performed, and how this process is regulated to ensure that recycling is confined exclusively to proteins that are toxic or unnecessary for ongoing cellular tasks. One challenge is that ubiquitination occurs rapidly, in only milliseconds. Schulman and her team devised methods to obtain 3D structure imaging of E3 ligases essentially “frozen” along the different steps of the ubiquitination process. Connecting the suite of structures, much like frames in a movie, allowed the visualization of the kinetic process of ubiquitination. Schulman’s team has also visualized how E3 ligases are kept off until needed, and how they are switched on by tweaking the structures of proteins destined for recycling and by signals to E3 ligases that such proteins should be ubiquitinated.

Ivan Đikić spearheaded the concept that ubiquitination affects proteins in many ways, not just marking them for degradation. Although specific types of ubiquitin chains were known to bind to the proteasome, the cellular shredding machine, Đikić uncovered that alternative types of chain linkages exert regulation of other processes, revealing ubiquitin as one of the most versatile cellular signals regulating virtually all cellular functions. He has contributed critically to discovering the spectrum of ubiquitin “readers”, enabling diverse ubiquitin functions. One of those functions is the regulation of a central quality control process in our cells: autophagy. Ubiquitin signals determine which cellular components (e.g. mitochondria, bacteria, protein aggregates) must be sent for destruction via autophagy. With these studies, he broke new ground in understanding the functions of both the ubiquitin and autophagy systems, and uncovered their relations to pathophysiological processes driving cancer, neurodegeneration, and infection.

Through their combined work, we have gained insights into diseases such as neurodegeneration and cancer. Recently, using complementary approaches, both groups were involved in revealing how bacteria and viruses evolved new types of ubiquitin signals and developed the capability to hijack the host ubiquitin system to drive the proliferation of pathogens and the spread of infections within the organism. Many compounds affecting ubiquitination and presenting high pharmacological activity have been identified at the basic research level and offer great clinical potential.

Prof. Ivan Đikić

Institute of Biochemistry II
Goethe University Medical Faculty
University Hospital Building 75
Theodor-Stern-Kai 7
60590 Frankfurt am Main
Germany


biochem2.com

Prof. Brenda Schulman

Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Martinsried


www.biochem.mpg.de