Behavior of Alzheimer-linked protein is revealed

Enzymes called kinases manage a wide range of cell processes, from metabolism, cell signaling, nutrient transport, and many others. Because they can affect so many different cell activities, kinases are tightly regulated within cells to make sure that the enzymes only act when necessary. Improperly activated kinases are linked to illnesses such as cancer and Alzheimer’s disease. A group of scientists from VIB, Vrije Universiteit Brussel (VUB) and Université Libre de Bruxelles (ULB) led by Prof. Tom Lenaerts (VUB-ULB) and prof. Nico van Nuland (VIB-VUB) has uncovered a new mechanism for controlling the activation of a kinase implicated in Alzheimer’s disease, generating novel insights into how to control this protein’s activity. The research was published in the high- profile journal Structure, a Cell Press periodical.

To make sure that the activities of kinase proteins are well-managed, proteins have evolved different methods to toggle them on and off by disrupting their interactions on a molecular level. Side chains are chemical groups directly attached to a protein’s main chain or backbone that affect both the shape and function of a protein. In their new research on the activation of a specific enzyme called Fyn, Prof. Lenaerts and his team were able to identify the specific toggling mechanism that this protein uses to ensure its own regulation, revealing for the first time the role that side chains play in the process. Their observations may be important to the development of Alzheimer-treatment therapies, as Fyn interacts with the protein Tau, which has been identified as a cause of the disease.

How cells switch their enzymes on and off

Just like the thermostats in our homes, which turn the heat on and off based on temperature changes, changes in the interactions between the modules defining protein structures activate and deactivate kinases. Using both experimental and predictive techniques, the multidisciplinary team uncovered a network of communicating protein residues inside cells that control Fyn’s activation. Research has shown that toggling off Fyn in mice with Alzheimer’s disease reduces memory problems in these mice.

Prof. Tom Lenaerts (VUB-ULB): “The insights presented by our research may provide important mechanistic knowledge of kinase regulatory systems, which could be used to develop new drugs that regulate Fyn’s activity in Alzheimer’s patients.”

The human side of excellent science

This research is especially poignant to the Belgian scientific community, as Prof. Nico van Nuland, co- author and a pioneer in this research field, was diagnosed only a few years ago with Amyotrophic Lateral Sclerosis (ALS). He has been fighting this disease with courage and optimism, providing crucial support to the entire research team. He possesses expert knowledge of nuclear magnetic resonance spectroscopy, which was crucial in the reported research. “Without his contributions, these results would have never been realized,” says Prof. Lenaerts.

Publication Dynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity, Huculeci et al., Structure 2016 Doi: 10.1016/j.str.2016.08.016.

Questions from patients A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: [email protected]. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

Note to the editor

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VIB Basic research in life sciences is VIB’s raison d’être. On the one hand, we are pushing the boundaries of what we know about molecular mechanisms and how they rule living organisms such as human beings, animals, plants and microorganisms. On the other, we are creating tangible results for the benefit of society. Based on a close partnership with five Flemish universities – , KU Leuven, , Vrije Universi0eit Brussel and University – and supported by a solid funding program, VIB unites the expertise of 75 research groups in a single institute. VIB’s technology transfer activities translate research results into new economic ventures which, in time, lead to new products that can be used in medicine, agriculture and other applications. VIB also engages actively in the public debate on biotechnology by developing and disseminating a wide range of science-based information about all aspects of biotechnology. More information: www.vib.be .

Vrije Universiteit Brussel The Vrije Universiteit Brussel (VUB) is a thriving university in the heart of and Europe, which in 1969-1970 split off from the Université Libre de Bruxelles (ULB), founded in 1834. VUB combines excellence in teaching with excellence in research. Several of its 150 research groups are topranked worldwide. The principle of independent research is central at VUB, but the quality of its undergraduate and graduate programs is no less important, as the university provides an environment where students are treated as individuals and supported in their personal development. Currently, VUB has some 9,000 students and 2,700 staff, divided over eight faculties and two Brussels campuses (in Etterbeek/Elsene and Jette). The VUB University Hospital is adjacent to the Medical Sciences campus in Jette and employs 3,000 people. More info: www.vub.ac.be/ .

ULB Multicultural and international, that's the Université libre de Bruxelles (ULB). A third of its students and researchers come from abroad, the ULB is like Brussels, a cosmopolitan center by excellence. With thirteen faculties, schools and specialized centers, the ULB operates in all disciplines. Research and education are optimally matched. This leads to numerous collaborations and privileged partnerships with leading foreign universities. The University distinguishes itself in a humanist approach to knowledge, through free, impartial research, and, in the words of Marie Curie, through its participation in fundamental research programmes. The university is proud to have won an array of awards that stand testament to its excellence, especially the four Nobel Prizes for science, 25 Francqui Prizes (out of 82), the highest honour in the sciences in Belgium, and 24 European Research Council grants.

Contact

Tom Lenaerts (VUB-ULB) Mobile: +32 486 93 19 96 Mail: [email protected]

Sooike Stoops (Expert Press and Public Communication VIB) Tel.: +32 9 244 66 11 Mobile: +32 474 289 252 Mail: [email protected]

Sicco Wittermans (Expert Press VUB) Tel.: +32 26 29 21 37 Mail: [email protected]

Nancy Dath (ULB Research Communication) Tel.: +32 2 650 92 03 Mail: [email protected]