Tanja Mittag, St. Jude Children’s Research Hospital, is one of the speakers at the Swedish Conference on Macromolecular Structure and Function conference, Sweprot, which takes place in Tällberg, Sweden on the 17-20th of June. There, she will speak about her research, which focuses on the process of phase separation.
– In phase separation, protein or other macromolecular solutions demix into two phases; a dense phase in which the macromolecule is concentrated, and a dilute phase which is relatively depleted of the macromolecule. When this happens you end up with viscous droplets of a highly concentrated protein solution in a dilute solution. It turns out that this process is extremely wide-spread in cells and compartmentalizes them. So, in addition to the many membrane-surrounded organelles in cells, there are membrane-less organelles (one prime example being the well-known nucleolus!), which we also call biomolecular condensates, and which are formed by phase separation.
– My lab studies how phase separation is encoded in proteins (not all proteins phase separate strongly), the effect of this process on biochemical function, and how dysregulation of phase separation can result in disease processes.
Can you give an example of a project of yours that you find extra interesting?
– Of course! In collaborations with my colleague Paul Taylor, who is a neurologist and cell biologist, we have been trying to understand why stress granules (which are a type of biomolecular condensate in the cytoplasm that is formed under stress conditions) are the crucibles for the formation of protein aggregates, the hallmark of neurodegenerative diseases such as ALS. It is mostly RNA-binding proteins that form these deposits in ALS and related diseases, and the RNA-binding proteins are sometimes found in dynamic stress granules, sometimes diffuse in the cell.
– What is it about the stress granules that leads RNA-binding proteins to aggregate within them? We showed that these RNA-binding proteins can phase separate, which is the mechanism underlying the formation of stress granules, and that phase separation strongly promotes aggregation. This is particularly the case for mutant proteins which have been found to lead to familial forms of ALS, i.e. the disease mutant proteins aggregated even more strongly in droplets. We proposed that the high local concentrations in the droplets in the test tube and in stress granules in cells could promote the aggregation of the proteins. We therefore proposed a mechanism for the molecular basis of certain types of ALS!
Tanja Mittag says that this work, which was published in 2015, prompted a lot of fundamental research into how phase separation is encoded in proteins, as this seems to enhance their chances of aggregating.
– We have been trying to understand the underlying rules conceptually, and we use quantitative biophysical characterizations to arrive there. This is work I am going to present at the Sweprot conference. I think it is important to be able to distinguish the interactions that drive phase separation from the interactions that drive pathological aggregation to eventually be able to develop therapeutics.
What is your background and how did you choose your research topic?
– I am trained as a biochemist and have been focused on the biophysics of protein-protein interactions through most of my advanced training. My scientific home is in NMR spectroscopy, and the rigorous biophysical training has allowed me to make the jump into many other biophysical techniques. But fundamentally I am driven by the desire to solve interesting biological problems. This is what gets me out of bed in the morning!
Who should listen to your talk at Sweprot?
– Everybody who is interested in how tiny protein molecules have effects on larger length scales by forming condensates! And everyone who would like to think about the conceptual underpinnings of phase separation. How does it actually work, and can we use these insights to learn more about the physical basis of cell biological processes?
Don’t miss the opportunity to listen to Tanja Mittag as well as other interesting speakers at the Sweprot meeting in Tällberg, Sweden on the 17-20th of June.